Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PRKN
Cytogenetic location: 6q26 Genomic coordinates (GRCh38): 6:161,347,417-162,727,766 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q26 | Adenocarcinoma of lung, somatic | 211980 | 3 | |
| Ovarian cancer, somatic | 167000 | 3 | ||
| Parkinson disease, juvenile, type 2 | 600116 | Autosomal recessive | 3 |
Parkin is a RING domain-containing E3 ubiquitin ligase involved in proteasome-dependent degradation of proteins. Parkin is also important for mitochondrial quality control by lysosome-dependent degradation of damaged mitochondria through autophagy, or mitophagy (summary by Yoshii et al., 2011).
Autosomal recessive juvenile parkinson disease-2 (PARK2; 600116) maps to chromosome 6q25.2-q27, as indicated by linkage to markers D6S305 and D6S253. The former was deleted in 1 Japanese patient with PDJ (Matsumine et al., 1997). By positional cloning within this microdeletion, Kitada et al. (1998) isolated a cDNA clone of 2,960 bp with a 1,395-bp open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin (191339) at the amino terminus and with a ring finger motif at the carboxy terminus. A 4.5-kb transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from 1 of the exon-4-deleted patients. Mutations in the newly identified gene appeared to be responsible for the pathogenesis of PDJ and, therefore, the protein product was designated 'parkin.'
The parkin protein comprises an N-terminal ubiquitin-like (UBL) domain and 2 C-terminal RING finger domains that are separated by an in-between ring (IBR) domain. The RING-IBR-RING (RBR) structure is highly conserved and found only in eukaryotes (Beasley et al., 2007).
Kitada et al. (2000) cloned mouse parkin, which encodes a deduced 464-amino acid protein that shares 83.2% identity with human parkin. They also identified a splice variant of mouse parkin that encodes a deduced 261-amino acid protein lacking the RING finger-like domain. Northern blot analysis detected parkin expression in mouse brain, heart, liver, skeletal muscle, kidney, and testis. Parkin expression was evident in 15-day mouse embryos and increased in later stages of development.
Kitada et al. (1998) found that the PARK2 gene spans more than 500 kb and has 12 exons.
Asakawa et al. (2001) determined that the parkin gene contains 12 exons and spans 1,380 kb. The longest intron, intron 1, is 284 kb. The 5-prime flanking region has no apparent TATA or CAAT box elements, but it has GC- and CpG-rich regions, as do the first exon and first intron. Asakawa et al. (2001) found that the PACRG gene (608427) lies in a head-to-head orientation with parkin. The 198-bp interval between them contains several putative regulatory elements, including SP1 (189906)-binding sites. Reporter gene assays confirmed that the upstream region contains positive regulatory elements.
West et al. (2003) reported that the parkin and PACRG genes are linked in a head-to-head arrangement on opposite DNA strands and share a common 5-prime flanking promoter region. The putative region of bidirectional transcription activation contains an AP4 (600743)-like site, a GC-rich region, and a MYC (190080)-like site.
Solution Structure
By NMR spectroscopy, Beasley et al. (2007) determined the 3-dimensional structure of the isolated IBR domain of parkin and found that the IBR domain has 2 zinc-binding sites. Zinc binding is required for the correct folding of the IBR domain, which is necessary for proper protein interactions and subsequent ubiquitination.
Protein Structure
Hristova et al. (2009) used limited proteolysis experiments on bacterially expressed and purified parkin to identify a domain, RING0, within the unique parkin domain sequence. RING0 comprises 2 distinct, conserved cysteine-rich clusters between cys150-cys169 and cys196-his215 consisting of CX(2-3)CX(11)CX(2)C and CX(4-6)CX(10-16)CX(2)(H/C) motifs. The positions of the cysteine/histidine residues in this region bear similarity to parkin RING1 and RING2 domains, as well as other E3 ligase RING domains. However, in parkin a 26-residue linker region separates the motifs, which is not typical of other RING domain structures. Further, the RING0 domain includes all but 1 of the sites of mutations resulting in autosomal recessive juvenile Parkinson disease known to that time between the ubiquitin-like and RBR regions of parkin. Using electrospray ionization mass spectrometry and inductively coupled plasma-atomic emission spectrometry analysis, Hristova et al. (2009) determined that the RING0, RING1, IBR, and RING2 domains each bind 2 Zn(2+) ions, the first observation of an E3 ligase with the ability to bind 8 metal ions. Removal of the zinc from parkin causes near complete unfolding of the protein, an observation that rationalizes cysteine-based mutations found throughout parkin, including RING0 C212Y (602544.0012), that form cellular inclusions and/or are defective for ubiquitination likely because of poor zinc binding and misfolding.
Crystal Structure
Trempe et al. (2013) described the crystal structure of full-length rat parkin in an autoinhibited state. RING0 occludes the ubiquitin acceptor site cys431 in RING2, whereas a repressor element of parkin binds RING1 and blocks its E2-binding site. Mutations that disrupted these inhibitory interactions activated parkin both in vitro and in cells.
To elucidate how phosphorylation of parkin by PINK1 (608309) activates the molecule, Gladkova et al. (2018) followed the activation of full-length human parkin by hydrogen-deuterium exchange mass spectrometry, which revealed large-scale domain rearrangement in the activation process, during which the phospho-ubiquitin-like (Ubl) domain rebinds to the parkin core and releases the catalytic RING2 domain. A 1.8-angstrom crystal structure of phosphorylated human parkin revealed the binding site of the phospho-Ubl on the unique parkin domain, involving a phosphate-binding pocket lined by mutations causing autosomal recessive juvenile parkinsonism. Notably, a conserved linker region between the ubiquitin-like domain and the unique parkin domain acts as an activating element that contributes to RING2 release by mimicking RING2 interactions on the unique parkin domain, explaining further autosomal recessive juvenile Parkinson mutations. Gladkova et al. (2018) concluded that their data showed how autoinhibition in parkin is resolved, and suggested a mechanism for how parkin ubiquitinates its substrates via an untethered RING2 domain.
The PARK2 gene maps to chromosome 6q25.2-q27, the region to which autosomal recessive juvenile parkinsonism maps (Kitada et al., 1998). By FISH, Tomac and Hoffer (2001) mapped the mouse Park2 gene to chromosome 17.
By Western blot analysis and immunohistochemistry, Huynh et al. (2000) showed that parkin is expressed in neuronal processes and cell bodies of neurons, but not glial cells, in the midbrain, basal ganglia, cerebral cortex, and cerebellum. Parkin assimilated with actin filaments (see 102560), suggesting that it is a cytoskeletal-associated protein. Parkin did not localize to the Golgi apparatus or to Lewy bodies in brains of Parkinson disease patients.
Cookson et al. (2003) found that wildtype parkin was homogeneously distributed throughout the cytoplasm of transfected human embryonic kidney cells, with a small amount of protein in the nucleus. Some mutant isoforms (e.g., A82E; 602544.0011) were also normally distributed. However, mutant isoforms (e.g., R275W; 602544.0017) within RING finger domain-1 of the parkin protein (residues 238 to 293) produced an unusual distribution of parkin, with large cytoplasmic and nuclear inclusions. The observation was replicated in primary cultured neurons, demonstrating by the accumulation/colocalization of cytoskeletal vimentin (VIM; 193060) that the inclusion bodies were aggresomes, a cellular response to misfolded protein.
By assaying for the activation of a dual-reporter plasmid transfected into a neuroblastoma cell line, West et al. (2003) identified a 35-bp site of bidirectional transcription activation within the overlapping PACRG/parkin promoter region. Using a gel shift assay, they found that a probe spanning the MYC consensus site within the activation region bound protein contained in substantia nigra nuclear extracts. Probes spanning the AP4 and GC-rich regions did not interact with nuclear protein in this assay.
Rubio de la Torre et al. (2009) reported that compound phosphorylation of parkin by both casein kinase I (CSNK1A1; 600505) and cyclin-dependent kinase-5 (CDK5; 123831) decreased parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reversed the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation was detected in distinct brain areas of individuals with sporadic PD and correlated with increases in the levels of p25 (CDK5R1; 603460), the activator of CDK5.
Da Costa et al. (2009) identified parkin as a transcriptional repressor of p53 (TP53; 191170) independent of its ubiquitin ligase function. Studies in mouse neurons and fibroblasts showed that overexpression of wildtype parkin protected cells from a variety of proapoptotic stimuli, including caspase-3 (CASP3; 600636) activation, in a p53-dependent manner. Overexpression of wildtype parkin induced marked reductions in p53 expression, transcriptional activity, promoter transactivation, and mRNA levels in a concentration-dependent manner. Studies of PD-related parkin mutations in human neuroblastoma cells showed that neither ligase-active nor ligase-dead mutants were able to reduce caspase-3 activity or p53 expression. Deletion and chromatin immunoprecipitation studies revealed that the Ring1 domain of wildtype parkin bound to and suppressed the p53 promoter. Pathologic studies of 2 PARK2 mutant brain samples showed increased p53 mRNA levels.
Rothfuss et al. (2009) found that parkin was associated physically with mitochondrial DNA (mtDNA) in proliferating as well as in differentiated SH-SY5Y neuroblastoma cells. In vivo, the association of parkin with mtDNA could be confirmed in brain tissue of mouse and human origin. Replication and transcription of mtDNA were enhanced in SH-SY5Y cells overexpressing the parkin gene. The ability of parkin to support mtDNA metabolism was impaired by pathogenic parkin point mutations. Parkin protected mtDNA from oxidative damage and stimulated mtDNA repair. Higher susceptibility of mtDNA to reactive oxygen species and reduced mtDNA repair capacity was observed in parkin-deleted fibroblasts from a PD patient. Rothfuss et al. (2009) proposed a role for parkin in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress.
Berger et al. (2009) isolated mitochondria from cells expressing either excess levels of human parkin or shRNA directed against endogenous parkin and then treated with peptides corresponding to the active Bcl2 homology-3 (BH3) domains of proapoptotic proteins. In both rodent and human neuroblastoma cell lines, expression levels of parkin were inversely correlated with cytochrome c release. Parkin was found associated with isolated mitochondria, but its binding per se was not sufficient to inhibit cytochrome c release. In addition, pathogenic parkin mutants failed to influence cytochrome c release. PINK1 (608309) expression had no effect on cytochrome c release, suggesting a divergent function for this autosomal recessive Parkinson disease-linked gene. Berger et al. (2009) proposed a specific autonomous effect of parkin on mitochondrial mechanisms governing cytochrome c release and apoptosis, which may be relevant to the selective vulnerability of certain neuronal populations in Parkinson disease.
Using transfected mouse embryonic fibroblasts, Yoshii et al. (2011) showed that parkin translocated to depolarized mitochondria and induced mitochondrial perinuclear clustering and proteasome-dependent degradation of the outer mitochondrial membrane proteins Tom70 (TOMM70; 606081), Tom40 (TOMM40; 608061), and Omp25 (SYNJ2BP; 609411), resulting in mitochondrial rupture. Parkin also appeared to induce autophagy of damaged mitochondria, resulting in the lysosome-dependent degradation of mitochondrial inner membrane and matrix proteins.
Chen and Dorn (2013) demonstrated that the mitochondrial outer membrane guanosine triphosphatase mitofusin-2 (MFN2; 608507) mediates parkin recruitment to damaged mitochondria. Parkin bound to MFN2 in a PINK1-dependent manner; PINK1 phosphorylated MFN2 and promoted its parkin-mediated ubiquitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Chen and Dorn (2013) concluded that MFN2 functions as a mitochondrial receptor for parkin and is required for quality control of cardiac mitochondria.
Hasson et al. (2013) elucidated regulators that have an impact on parkin translocation to damaged mitochondria with genomewide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 (607980) as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. Hasson et al. (2013) also discovered that HSPA1L (140559) and BAG4 (603884) have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3 (615609), found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation.
Bingol et al. (2014) reported that USP30 (612492), a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin and protein kinase PINK1, which are encoded by 2 genes associated with Parkinson disease (see 168600). Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks the parkin's ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or Pink1-deficient flies. Knockdown of Usp30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function, and organismal survival. Bingol et al. (2014) concluded that USP30 inhibition is potentially beneficial for treating Parkinson disease by promoting mitochondrial clearance and quality control.
Lazarou et al. (2015) used genome editing to knock out 5 autophagy receptors in HeLa cells and demonstrated that 2 receptors previously linked to xenophagy, NDP52 (604587) and optineurin (602432), are the primary receptors for PINK1- and parkin-mediated mitophagy. PINK1 recruits NDP52 and optineurin but not p62 (SQSTM1; 601530) to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1 (603168), DFCP1 (ZNFN2A1; 605471), and WIPI1 (609224) to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3 (MAP1LC3A; 601242). Lazarou et al. (2015) concluded that their observations support a model in which PINK1-generated phosph-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal.
Gong et al. (2015) found that Pink1 (608309)-Mfn2 (608507)-parkin-mediated mitophagy directs the change in mitochondrial substrate preference in developing mouse hearts from from carbohydrates to fatty acids. A Mfn2 mutant lacking Pink1 phosphorylation sites necessary for parkin binding (Mfn2 AA) inhibited mitochondrial parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac Parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five-week-old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal parkin-mediated mitophagy and replacement by mature adult mitochondria. Gong et al. (2015) concluded that mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts.
Hoshino et al. (2019) developed a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and promitophagy triggers, and identified numerous components of parkin-dependent mitophagy. Unexpectedly, they found that the ANT (see ANT1, 103220) complex was required for mitophagy in several cell types. Whereas pharmacologic inhibition of ANT-mediated ADP/ATP exchange promoted mitophagy, genetic ablation of ANT paradoxically suppressed mitophagy. Notably, ANT promoted mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex was required for inhibition of the presequence translocase TIM23 (605034), which led to stabilization of PINK1, in response to bioenergetic collapse. ANT modulated TIM23 indirectly via interaction with TIM44 (605058), which regulated peptide import through TIM23. Mice that lacked ANT1 showed blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogated binding to TIM44 and TIM23 and inhibited mitophagy.
Parkin as a Ubiquitin-Protein Ligase
Kitada et al. (1998) suggested that parkin may function similarly to ubiquitin family members, and its defect in PDJ may interfere with the ubiquitin-mediated proteolytic pathway leading to the death of nigral neurons.
Shimura et al. (2000) reported that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating protein Ubch7 (UBE2L3; 603721), and that mutant parkin from patients with autosomal recessive juvenile parkinsonism shows loss of the ubiquitin-protein ligase activity. The findings indicated that accumulation of proteins causes a selective neural cell death without formation of Lewy bodies, which are absent in PDJ.
Zhang et al. (2000) showed that parkin binds to the E2 ubiquitin-conjugating enzyme-8 (UBCH8; 603890) through its C-terminal ring finger. Parkin has ubiquitin-protein ligase activity in the presence of UBCH8. Parkin also ubiquitinates itself and promotes its own degradation.
Imai et al. (2001) identified PAELR (GPR37; 602583) as a protein that interacts with parkin. When overexpressed in cells, PAELR tends to become unfolded, insoluble, and ubiquitinated in vivo. The insoluble PAELR leads to unfolded protein-induced cell death. Parkin specifically ubiquitinates PAELR in the presence of ubiquitin-conjugating enzymes resident in the endoplasmic reticulum and promotes the degradation of insoluble PAELR, resulting in suppression of the cell death induced by PAELR overexpression. Moreover, the authors showed that the insoluble form of PAELR accumulates in the brains of PDJ patients. They concluded that unfolded PAELR is a substrate of parkin and that the accumulation of PAELR may cause selective neuronal death in PDJ.
Accumulation of PAELR in the endoplasmic reticulum (ER) of dopaminergic neurons induces ER stress leading to neurodegeneration. Imai et al. (2002) showed that CHIP (607207), HSP70 (140550), parkin, and PAELR formed a complex in vitro and in vivo. The amount of CHIP in the complex increased during ER stress. CHIP promoted the dissociation of HSP70 from parkin and PAELR, thus facilitating parkin-mediated PAELR ubiquitination. Moreover, CHIP enhanced parkin-mediated in vitro ubiquitination of PAELR in the absence of HSP70. CHIP also enhanced the ability of parkin to inhibit cell death induced by PAELR. The authors concluded that CHIP is therefore a mammalian E4-like molecule that positively regulates parkin E3 activity.
Tsai et al. (2003) found that parkin colocalized with polyglutamine (poly(Q))-expanded huntingtin (613004) in Huntington disease (HD; 143100) brains and in transgenic mouse models of HD. In cultured human and mouse cells, parkin promoted ubiquitination and degradation of model poly(Q) proteins, and it formed a complex with the poly(Q) protein, HSP70, and the proteasome. HSP70 enhanced parkin binding and ubiquitination of poly(Q) proteins in vitro, suggesting that HSP70 may recruit misfolded proteins as substrates for parkin E3 ubiquitin ligase activity. Tsai et al. (2003) hypothesized that parkin functions to relieve ER stress by preserving proteasome activity in the presence of misfolded proteins. Thus, loss of parkin function and the resulting proteasomal impairment may contribute to the accumulation of toxic aberrant proteins and neurodegeneration in Parkinson disease.
Shimura et al. (2001) hypothesized that alpha-synuclein (SNCA; 163890) and parkin interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in PDJ. Shimura et al. (2001) identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UBCH7 as its associated E2 ubiquitin-conjugating enzyme, and a novel 22-kD glycosylated form of alpha-synuclein (alpha-Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive Parkinson disease failed to bind alpha-Sp22. In an in vitro ubiquitination assay, alpha-Sp22 was modified by normal, but not mutant, parkin into polyubiquitinated, high molecular weight species. Accordingly, alpha-Sp22 accumulated in a nonubiquitinated form in parkin-deficient Parkinson disease brains. Shimura et al. (2001) concluded that alpha-Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathologic accumulation of alpha-Sp22. These findings demonstrated a critical biochemical reaction between the 2 Parkinson disease-linked gene products and suggested that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional Parkinson disease (PD; 168600).
Chung et al. (2001) showed that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein synphilin-1 (603779). Coexpression of alpha-synuclein, synphilin-1, and parkin resulted in the formation of Lewy body-like ubiquitin-positive cytosolic inclusions. They further showed that familial mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. Chung et al. (2001) concluded that their results provided a molecular basis for the ubiquitination of Lewy body-associated proteins and linked parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.
Hyun et al. (2002) transfected wildtype and mutant PARK2 into a human neuroblastoma cell line and a teratocarcinoma cell line with cholinergic characteristics. Increased expression of wildtype PARK2 in both lines increased proteasome activity and decreased the level of modified proteins that are usually degraded within proteasomes, including carbonylated, nitrated, and ubiquitinated proteins. Overexpression of PARK2 containing the exon 3-5 deletion, thr240-to-arg (T240R; 602544.0003), or gln311-to-ter (Q311X; 602544.0004) mutations increased the activity of neuronal nitric oxide synthase (163731) and increased the level of nitrated proteins and reactive nitrogen species. Overexpression of the mutations increased oxidative stress as indicated by decreased levels of reduced glutathione and elevated levels of oxidative damage to proteins and lipids. However, the mutations did not effect antioxidant enzyme activities. The degradation of mutant PARK2 proteins was slower than that of the wildtype protein, and both could be blocked by the proteasome inhibitor lactacystin. Hyun et al. (2002) also determined that whereas the T240R or Q311X mutations resulted in PARK2 with no ubiquitin-protein ligase activity, PARK2 with the exon 3-5 deletion was fully active. These findings suggested that the pathologic effects of these mutations are independent of their effects on ligase activity.
Mengesdorf et al. (2002) showed that, in mice, transient focal cerebral ischemia of 1-hour duration induced marked depletion of parkin protein levels after reperfusion, but that ischemia did not cause lower protein levels of the E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9 (UBE2I; 601661). After 3 hours of reperfusion, when parkin protein levels were already reduced to less than 40% of control, ATP levels were almost completely recovered from ischemia and no DNA fragmentation was observed, suggesting that parkin depletion preceded development of neuronal cell death. Mengesdorf et al. (2002) interpreted the data as suggesting that ischemia-induced depletion of parkin protein may contribute to the pathologic process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.
Darios et al. (2003) induced overproduction of parkin in PC12 cells. In this cell line, neuronally differentiated by nerve growth factor (see 162030), parkin overproduction protected against cell death mediated by ceramide, but not by a variety of other cell death inducers. Protection was abrogated by the proteasome inhibitor epoxomicin and disease-causing variants, indicating that protection was mediated by the E3 ubiquitin ligase activity of parkin. Parkin appeared to act by delaying mitochondrial swelling, cytochrome c release, and caspase-3 (CASP3; 600636) activation observed in ceramide-mediated cell death. Subcellular fractionation demonstrated enrichment of parkin in the mitochondrial fraction and an association with the outer mitochondrial membrane. The authors suggested that parkin may promote the degradation of substrates localized in mitochondria and involved in the late mitochondrial phase of ceramide-mediated cell death.
Staropoli et al. (2003) demonstrated that parkin associates with the F-box proteins FBXW7 (606278) and cullin-1 (603134) in a distinct ubiquitin ligase complex. FBXW7 serves to target the ligase activity to cyclin E (123837), a protein previously implicated in the regulation of neuronal apoptosis. In cells transfected with the parkin T240R mutation (602544.0003), parkin deficiency potentiated the accumulation of cyclin E in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate and promoted their apoptosis. Furthermore, parkin overexpression attenuated cyclin E accumulation in toxin-treated neurons and protected them from apoptosis.
Muqit et al. (2004) showed that endogenous parkin was present in aggresomes of cultured human neuroblastoma cells stressed by dopamine, proteasome inhibition, and a proapoptotic stimulus. Vimentin was invariably collapsed around the aggresome, but detection of ubiquitin (191339) was variable, depending on the stress. Cells that stably overexpressed human wildtype parkin formed fewer aggresomes upon stress, whereas overexpression of PDJ-causing PARK2 mutants had no effect on stress-induced aggresome formation. Prevention of aggresome formation by overexpression of wildtype parkin was not always associated with beneficial effect on neuronal survival. Muqit et al. (2004) suggested that parkin may be important for aggresome formation in human neuronal cells.
Chung et al. (2004) demonstrated that parkin is S-nitrosylated in vitro as well as in vivo in a mouse model of Parkinson disease and in brains of patients with Parkinson disease and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. Chung et al. (2004) concluded that the inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
Jiang et al. (2004) showed that overexpression of parkin protected a human dopaminergic neuroblastoma cell line against apoptosis induced by dopamine or 6-hydroxydopamine but not by hydrogen peroxide or rotenone. Parkin significantly attenuated dopamine-induced activation of c-Jun N-terminal kinase (MAPK8; 601158) and CASP3. It also decreased the level of reactive oxygen species (ROS) and protein carbonyls in the cell. Inhibiting dopamine uptake through dopamine transporter (126455) or treating the cell with antioxidants significantly reduced oxidative stress and dopamine toxicity. PD-linked mutations of parkin significantly abrogated the protective effect of wildtype parkin, as well as its ability to suppress ROS and protein carbonylation. As parkin mutants used in the study exhibit either no significant E3 ligase activity towards known substrates, or defective interaction with the 26S proteasome (see 602706), it appeared to Jiang et al. (2004) that the protective function of parkin against dopamine toxicity is dependent on its E3 ligase activity or its interaction with proteasome. Jiang et al. (2004) suggested that parkin may protect against dopamine toxicity by decreasing oxidative stress and ensuing activation of apoptotic programs such as the MAPK8/caspase pathway and that the protective function of parkin may be important for the survival of dopaminergic neurons, which are constantly threatened by oxyradicals produced during dopamine oxidation.
In autosomal recessive juvenile parkinsonism, mutation in the PARK2 gene is linked to death of dopaminergic neurons. Yao et al. (2004) showed both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wildtype parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in the E3 ubiquitin ligase activity of parkin leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. Yao et al. (2004) concluded that these findings may provide a molecular link between the free radical toxicity and protein accumulation in sporadic Parkinson disease.
Moore et al. (2005) showed that pathogenic mutant forms of DJ1 (602533) specifically but differentially associate with parkin. Chemical crosslinking showed that pathogenic DJ1 mutants exhibited impairment in homodimer formation, suggesting that parkin may bind to monomeric DJ1. Parkin failed to specifically ubiquitinate and enhance the degradation of L166P (602533.0002) and M26I (602533.0003) mutant DJ1, but instead promoted their stability in cultured cells. Oxidative stress also promoted an interaction between DJ1 and parkin, but this did not result in the ubiquitination or degradation of DJ1. DJ1 levels were increased in the insoluble fraction of sporadic PD/DLB brains, but were reduced in the insoluble fraction of parkin-linked autosomal recessive juvenile-onset PD brains. The authors proposed that DJ1 and parkin may be linked in a common molecular pathway at multiple levels.
Lipton et al. (2005) found that S-nitrosylation of parkin was present at detectable levels in brains of patients with Parkinson disease, but found that S-nitrosylation increased, rather than decreased, the ubiquitin E3 ligase activity of parkin. Lipton et al. (2005) suggested that several technical differences may explain the apparent discrepancy between their results (Yao et al., 2004) and those of Chung et al. (2004). Within the first few hours of S-nitrosylation of parkin, Lipton et al. (2005) observed increased ubiquitin E3 ligase activity for both parkin itself and other substrates such as synphilin-1 (603779), which can be a component of Lewy bodies. This increased E3 ligase activity was followed by a gradual decrease in activity. Lipton et al. (2005) suggested that their observations of an initial increase in parkin E3 ligase activity could be explained by their looking at earlier time points after S-nitrosylation than did Chung et al. (2004). Chung et al. (2005) responded to the comments of Lipton et al. (2005) and confirmed that parkin S-nitrosylation enhances its E3 ligase activity at earlier time points but inhibits its E3 ligase activity at later time points, even when assays are performed at a more physiologic oxygen concentration of 5%. Thus, Chung et al. (2005) concluded that the enhancement of parkin's E3 ligase activity by S-nitrosylation appears to be an important mechanism by which parkin's function is regulated.
Using a yeast 2-hybrid system and coimmunoprecipitation methods, Huynh et al. (2003) determined that synaptotagmin XI (SYT11; 608741) interacts with parkin. Parkin binds to the C2A and C2B domains of synaptotagmin XI, resulting in the polyubiquitination of synaptotagmin XI. Truncated and missense-mutated parkins reduced parkin-synaptotagmin XI binding affinity and ubiquitination. Parkin-mediated ubiquitination also enhanced the turnover of synaptotagmin XI. In sporadic Parkinson disease brain sections, synaptotagmin XI was found in the core of Lewy bodies. The interaction of synaptotagmin XI with parkin suggests a role for parkin in the regulation of the synaptic vesicle pool and in vesicle release. The authors hypothesized that functional loss of parkin could affect multiple proteins controlling vesicle pools, docking, and release, and possibly explain the deficits in dopaminergic function seen in patients with parkin mutations.
Corti et al. (2003) demonstrated that parkin interacts with, ubiquitylates, and promotes the degradation of p38 (JTV1; 600859), a key structural component of the mammalian aminoacyl-tRNA synthetase complex. Ubiquitylation of p38 was abrogated by truncated variants of parkin lacking essential functional domains, but not by the pathogenic lys161-to-asn point mutant (602544.0008). Expression of p38 in COS-7 cells resulted in the formation of aggresome-like inclusions in which parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, parkin promoted the formation of ubiquitylated p38-positive inclusions. Overexpression of p38 in SH-SY5Y cells caused significant cell death against which parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of Lewy bodies in idiopathic Parkinson disease. The authors suggested that p38 may play a role in the pathogenesis of Parkinson disease.
Kalia et al. (2004) demonstrated that rat Bag5 (603885) directly interacts with Hsp70 and parkin. Bag5 inhibited both Hsp70-mediated refolding of misfolded proteins and parkin E3 ubiquitin ligase activity, and enhanced the sequestration of parkin in protein aggregates. In rats, overexpression of Bag5 resulted in increased death of dopaminergic neurons compared to controls, whereas overexpression of an inhibitory mutant Bag5 resulted in increased dopaminergic survival. Kalia et al. (2004) concluded that Bag5 is a negative regulator of both Hsp70 and parkin function that sensitizes dopaminergic neurons to injury-induced death and thus promotes neurodegeneration.
Dopamine is known to be a highly reactive molecule that possesses the greatest propensity for oxidation among the catecholamines. Dopamine can readily oxidize to form multiple reactive oxygen species as well as the protein-modifying dopamine quinone. LaVoie et al. (2005) found that endogenous dopamine covalently modified parkin in rodent and human dopaminergic cells, resulting in parkin insolubility and inactivation of its E3 ubiquitin ligase function. Increased parkin aggregates were identified in the caudate and cerebral cortex of patients with sporadic Parkinson disease. Catechol-modified parkin was also identified in the substantia nigra of normal human brains. LaVoie et al. (2005) concluded that parkin is vulnerable to modification by dopamine, and suggested that dopamine-induced loss of parkin represents a possible mechanism contributing to the selective degeneration of nigral neurons over time.
Smith et al. (2005) demonstrated that parkin interacts with LRRK2 (609007). LRRK2 interacted preferentially with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Coexpression of LRRK2 and parkin increased cytoplasmic protein aggregates that contained LRRK2 and enhanced the ubiquitination of these aggregates. Expression of mutant LRRK2 induced apoptotic cell death in human SH-SY5Y neuroblastoma cells and in mouse cortical neurons in vitro.
Dachsel et al. (2005) identified PSMA7 (606607) as an interacting partner of parkin. Coimmunoprecipitation experiments showed that the interaction occurred between residues 179 to 248 of PSMA7 and the C terminus of PARKIN, including the IBR-RING2 motif. Biochemical studies revealed that PSMA7 was not a substrate for parkin-dependent ubiquitylation.
Pawlyk et al. (2003) demonstrated that parkin solubility in the human brain becomes altered with age. Given that many parkin mutations resulting in familial PD also alter its solubility, Wang et al. (2005) demonstrated that several PD-linked stressors, including neurotoxins, paraquat, nitric oxide, dopamine, and iron, induced alterations in parkin solubility and resulted in its intracellular aggregation. Furthermore, the depletion of soluble, functional forms of parkin was associated with reduced proteasomal activities and increased cell death. Wang et al. (2005) suggested that exogenously introduced stress (as well as endogenous dopamine) could affect the native structure of parkin, promote its misfolding, and concomitantly compromise its protective functions. Wang et al. (2005) considered the preservation of proteasome activity, dependent on its E3 ligase activity, as a plausible mechanism for the protective effect of parkin.
Fallon et al. (2006) found that treatment of mammalian cells with human EGF (131530) stimulated parkin binding to both Eps15 (600051) and Egfr (131550) and promoted parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like domain to the Eps15 ubiquitin-interacting motifs (UIMs) was required for parkin-mediated Eps15 ubiquitination. Egfr endocytosis and degradation were accelerated in parkin-deficient cells, and Egfr signaling via the PI3K (see 171834)-Akt (164730) pathway was reduced in parkin-knockout mouse brain. Fallon et al. (2006) proposed that by ubiquitinating EPS15, parkin interferes with the ability of the EPS15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI3K-AKT signaling.
Um et al. (2006) showed that parkin interacted with and ubiquitinated RANBP2 (601181), a SUMO-related E3 ligase localized in the cytoplasmic filament of the nuclear pore complex. RANBP2 was degraded through the proteasomal complex following its ubiquitination by parkin. Parkin also controlled the intracellular levels of sumoylated HDAC4 (605314) as a result of the ubiquitination and degradation of RANBP2.
Using a protein pull-down strategy, Trempe et al. (2009) found that the UBL domain of parkin bound endophilins A1 (SH3GL2; 604465), A2 (SH3GL1; 601768), and A3 (SH3GL3; 603362) in mouse brain lysates. Binding was mediated by the SH3 domain of endophilin A1 and a highly conserved C-terminal motif (PxRK) of the parkin UBL domain. The parkin UBL domain bound the SH3 domains of several other BAR domain-containing proteins involved in vesicle trafficking, but it did not bind the SH3 domains of proteins lacking a BAR domain. Biochemical analysis revealed that the flexible C-terminal tail of the parkin UBL domain became structured upon binding the SH3 domain of endophilin A1. Phosphorylation promoted the interaction between endogenous parkin and endophilin A1 in mouse brain synaptosomes, which in turn led to increased levels of ubiquitinated synaptic proteins in wildtype mice, but not in parkin-knockout mice. Trempe et al. (2009) concluded that BAR-SH3 proteins, like the endophilins, are involved in parkin-mediated synaptic ubiquitination.
Burns et al. (2009) tested whether the ubiquitin ligase activity of parkin could lead to reduction of the intracellular human A-beta-42 (APP; 104760) fragments that accumulate in Alzheimer disease (AD; 104300). Lentiviral constructs encoding either human parkin or human A-beta-42 were used to infect human neuroblastoma M17 cells. Parkin expression resulted in reduction of intracellular human A-beta-42 levels and protected against its toxicity in M17 cells. Coinjection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin coexpression reduced human A-beta-42 levels and A-beta-42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing A-beta-42 levels. Incubation of A-beta-42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of A-beta/ubiquitin complexes. Burns et al. (2009) concluded that parkin promotes ubiquitination and proteasomal degradation of intracellular A-beta-42 and demonstrated a protective effect in neurodegenerative diseases with A-beta deposits.
Xiong et al. (2009) demonstrated that parkin, PINK1 (608309), and DJ1 (602533) interact and form an approximately 200-kD functional ubiquitin E3 ligase complex in human primary neurons. PINK1 was shown to increase the activity of parkin, which degrades itself via the ubiquitin-proteasome system. Pathogenic PINK1 (G309D; 608309.0001) did not promote ubiquitination and degradation of parkin or the parkin substrate synphilin-1 (603779) in transfected cells. Expression of DJ1 increased PINK1 expression, perhaps acting as a stabilizer. Overexpression of parkin substrates or heat shock treatment resulted in parkin accumulation in Pink1- or Dj1-deficient murine cells, and pathogenic parkin mutations resulted in a reduced ability to promote degradation of parkin substrates, all suggesting a decrease in E3 ubiquitin activity. Xiong et al. (2009) suggested that this complex promotes degradation of un- or misfolded proteins, including parkin, and that disruption of the activity of this complex leads to accumulation of abnormal proteins and increased susceptibility to oxidative stress, which is toxic to neurons and may lead to Parkinson disease.
Narendra et al. (2010) found that the expression of PINK1 in mitochondria is regulated by voltage-dependent proteolysis to maintain low levels, and that depolarization results in rapid accumulation of PINK1 on damaged mitochondria. In HeLa cells and mouse and human neuronal cells, PINK1 accumulation was both necessary and sufficient to recruit parkin to the mitochondria, where parkin induced autophagy of damaged mitochondria. PD-associated mutations in both PARK2 and PINK1 disrupted parkin recruitment and parkin-induced mitophagy at distinct steps. The findings indicated that PINK1 acts upstream of parkin in a conserved pathway critical for the maintenance of mitochondrial integrity and function.
In HeLa cells and human neuroblastoma cells, Geisler et al. (2010) found that PD-associated parkin mutations disrupted the normal sequential translocation of parkin to the mitochondria and/or clearing of sequestered mitochondria in response to chemically-induced dissipation of the mitochondrial membrane potential. Parkin and PINK1 coimmunoprecipitated in neuroblastoma cells, and functional PINK1 kinase activity was required for proper translocation of parkin to damaged mitochondria for mitophagy. Wildtype parkin formed polyubiquitin chains linked through lys27 and lys63 of ubiquitin as a crucial step in autophagy of mitochondria. The ubiquitination required the ubiquitin-binding protein SQSTM1 (601530) and involved ubiquitination of VDAC1 (604492) on the mitochondrial membrane. Importantly, PD-associated parkin variants interrupted this mitophagy process at distinct steps. The findings described a link between mitochondrial damage, ubiquitination, and selective autophagy of mitochondria. Disruption of the process by mutations resulted in failure of mitochondrial clearance, which likely plays a role in the pathogenesis of PD.
Sha et al. (2010) reported that PINK1 regulated the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. Phosphorylation of parkin by PINK1 activated parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhanced parkin-mediated ubiquitin signaling through the I-kappa-B kinase/nuclear factor kappa-B (NF-kappa-B) pathway. The ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling was impaired by PD-linked pathogenic PINK1 mutations. Sha et al. (2010) proposed a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicated the deregulation of the PINK1/parkin/NF-kappa-B neuroprotective signaling pathway in the pathogenesis of PD.
An association between Gaucher disease (GD; 230800) and PD has been demonstrated by the concurrence of PD in some GD patients and the identification of beta-glucosidase (GBA; 606463) mutations in some probands with sporadic PD. Ron et al. (2010) showed that mutant GBA variants associated with parkin, and that wildtype parkin, but not its RING finger mutants, affected the stability of mutant GBA variants. Parkin also promoted the accumulation of mutant GBA in aggresome-like structures and was involved in lys48 (K48)-mediated polyubiquitination of GBA mutants, thus indicating its function as an E3 ligase. The authors suggested that involvement of parkin in the degradation of mutant beta-glucosidase may explain the concurrence of GD and PD.
Choo et al. (2011) found that parkin was increased in the brains of Pink1-null mice due to a decrease in parkin's E3 ligase activity. Levels of another parkin substrate, JTV1 (AIMP2; 600859), were also increased in Pink1-null mice. The findings supported a previous study (Xiong et al., 2009) which found that the parkin/PINK1/DJ1 complex functions as an E3 ligase to promote degradation of parkin substrates and that PINK1 plays a crucial role in regulating parkin E3 ligase activity.
Wenzel et al. (2011) showed that, unlike many ubiquitin-conjugating enzymes (E2s) that transfer ubiquitin with RINGs, UBCH7 (603721) lacks intrinsic ubiquitin ligase (E3)-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin and human homolog of ariadne (HHARI; 605624). Found in all eukaryotes, RBRs regulate processes such as translation and immune signaling. RBRs contain a canonical C3HC4-type RING, followed by 2 conserved cys/his-rich zinc-binding domains, in-between-RING (IBR) and RING2 domains, which together define this E3 family. Wenzel et al. (2011) showed that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer ubiquitin through an obligate thioester-linked ubiquitin, requiring a conserved cysteine residue in RING2. Wenzel et al. (2011) concluded that their results defined the functional cadre of E3s for UBCH7, an E2 involved in cell proliferation and immune function, and indicated a novel mechanism for an entire class of E3s.
Parkin is S-nitrosylated by excessive nitric oxide (NO) in a reaction that transfers an NO group to critical cysteine thiol(s) to regulate E3 ubiquitin ligase activity. This can trigger aberrant protein accumulation and contribute to neuronal death in PD. In cellular studies, Meng et al. (2011) found that oxidation induced by inhibition of mitochondrial complex I or by H2O2 resulted in increased sulfonation and aggregation of parkin. Most (73%) of the sulfinated/sulfonated cysteines in parkin were in the RING and IBR domains, including 6 cysteines found to be mutated in Parkinson disease: cys212, cys253, cys268, cys289, cys431 (602544.0023), and cys441. Oxidative stress resulted in a cycle of increased autoubiquitination of parkin followed by decreased E3 ligase activity and ultimately an increase in insoluble parkin. Rats exposed to neurotoxins showed an increase in inclusion body-like parkin immunoreactivity in the striatum compared to controls, and a similar pattern of parkin immunoreactivity was observed in monkeys exposed to the neurotoxin MPTP. Human neural stem cells transplanted into these monkeys appeared to diminish parkin aggregation. Increased insoluble and sulfonated parkin was also found in postmortem brains from humans with Parkinson disease. The findings delineated a posttranslational mechanism in which parkin is modified chemically in response to exposure to oxidative stress, resulting in the accumulation of Lewy body-like aggregates.
Sarraf et al. (2013) used quantitative diGly capture proteomics to elucidate the ubiquitylation site specificity and topology of PARKIN-dependent target modification in response to mitochondrial depolarization. Hundreds of dynamically regulated ubiquitylation sites in dozens of proteins were identified, with strong enrichment for mitochondrial outer membrane proteins, indicating that PARKIN dramatically alters the ubiquitylation status of the mitochondrial proteome. Using complementary interaction proteomics, Sarraf et al. (2013) found depolarization-dependent PARKIN association with numerous mitochondrial outer membrane targets, autophagy receptors, and the proteasome. Mutation of the PARKIN active site residue C431 (C431F; 602544.0023), which has been found in Parkinson disease patients, largely disrupts these associations. Structural and topologic analysis revealed extensive conservation of PARKIN-dependent ubiquitylation sites on cytoplasmic domains in vertebrate and Drosophila mitochondrial outer membrane proteins.
Manzanillo et al. (2013) noted that genetic polymorphisms in the PARK2 regulatory region are associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella enterica serovar Typhi. Manzanillo et al. (2013) showed that parkin has a role in ubiquitin-mediated autophagy of M. tuberculosis. Both parkin-deficient mice and flies are sensitive to various intracellular bacterial infections, indicating that parkin has a conserved role in metazoan innate defense. Manzanillo et al. (2013) concluded that their work revealed an unexpected functional link between mitophagy and infectious disease.
Using immunoprecipitation and protein pull-down assays, Sul et al. (2013) found that parkin interacted with FAF1 (604460) in SH-SY5Y human neuroblastoma cells. Deletion analysis revealed that the UB1 domain of FAF1 and the N-terminal half of parkin, which includes a ubiquitin-like domain and RING1 domain, were required for the interaction. Parkin overexpression significantly increased ubiquitination of FAF1. Parkin used UBCH7 as the E2 ubiquitin-conjugating enzyme for lys48-linked ubiquitination of FAF1, which targeted FAF1 for proteasomal degradation. Exposure of SH-SY5Y cells to the PD-inducing neurotoxin 1-methyl-4-phenylpyridinium caused FAF1-dependent cell death via JNK1 (MAPK8) and CASP3 activation and generation of reactive oxygen species. Expression of wildtype parkin reduced FAF1 overexpression and attenuated the cellular effects of FAF1 in a dose-dependent manner.
Koyano et al. (2014) reported that ubiquitin is the genuine substrate of PINK1 (608309). PINK1 phosphorylated ubiquitin at ser65 both in vitro and in cells, and a ser65 phosphopeptide derived from endogenous ubiquitin was detected in cells only in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (UBE2L3; 603721) and ubiquitin in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Koyano et al. (2014) concluded that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity, and that phosphorylated ubiquitin is a parkin activator.
Gao et al. (2015) identified BNIP3L (605368) as a mitochondrial PARK2 substrate and showed that ubiquitinated BNIP3L recruited cytosolic NBR1 (166945) to damaged mitochondria, thereby targeting the organelle for degradation. Knockdown of either NBR1 or BNIP3L in HEK293A cells disrupted degradation of mitochondria damaged by inhibition of oxidative phosphorylation. In contrast, inhibition of mitochondrial complex I induced BNIP3L degradation and caused retention of damaged mitochondria.
Fragile Site FRA6E and Parkin as a Tumor Suppressor Gene
Loss of heterozygosity (LOH) analysis of the long arm of chromosome 6 identified several regions of loss in cancers, including ovarian cancer (167000) and breast cancer (114480). To identify tumor suppressor gene(s) associated with the LOH observed on chromosome 6q25-q27, Cesari et al. (2003) constructed a contig derived from the sequences of BAC/P1 clones defined by the genetic interval D6S1581 to D6S1008. Sequence analysis of this contig found it to contain 8 known genes, including the complete genomic structure of PARK2. LOH analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%). Both loci exhibited the highest frequency of LOH in this study and each was located within the PARK2 genomic structure. Whereas mutation analysis revealed no missense substitutions, expression of the PARK2 gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, the identification of 2 truncating deletions in 3 of 20 ovarian tumor samples, as well as homozygous deletion of exon 2 in 2 lung adenocarcinoma (608935) lines, supported the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of PARK2 in these samples. The data suggested that the LOH observed at 6q25-q26 may contribute to the initiation and/or progression of cancer by inactivating or reducing the expression of the PARK2 gene. Because PARK2 maps to FRA6E, one of the most active common fragile sites in the human genome (Smith et al., 1998), it may represent another example of a large tumor suppressor gene, like FHIT (601153) and WWOX (605131), located at a common fragile site. An Editorial Expression of Concern was published regarding the article by Cesari et al. (2003) because it appeared that Figures 2a and 2b, beta-actin panel, had duplicated bands. The authors stated that 'because this issue was first raised more than 10 years after publication, the original data are not available to confirm whether an error was made in the figure construction' but that 'any error in figure construction does not affect their scientific conclusions.'
Denison et al. (2003) pointed to the striking similarities among the large genes in the common fragile site (CFS) loci: FHIT at 3p14.2, WWOX at 16q23, and Parkin at 6q26. In a variety of cancer types, the presence in both FHIT and WWOX of alternative transcripts with whole exon deletions have been found. Various whole exon duplications and deletions have been identified in PARK2 in juvenile and early-onset Parkinson patients. The authors found that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian tumors were heterozygous for the duplication or deletion of 1 or more parkin exons. Additionally, 3 of 23 (13%) nonovarian tumor-derived cell lines were found to have a duplication or deletion of 1 or more parkin exons. Diminished or absent parkin expression was observed in most of the ovarian cancer cell lines when studies with antibodies were performed. Denison et al. (2003) suggested that parkin, like FHIT and WWOX, may represent a tumor suppressor gene.
Schlehe et al. (2008) found that misfolding of human parkin led to either formation of detergent-insoluble parkin aggregates or to parkin destabilization leading to accelerated proteasomal degradation. Destabilization appeared to be dominant over formation of insoluble aggregates. The proper folding of parkin was specifically dependent on phe463 near the C terminus.
In a retrospective study of 431 individuals with early-onset Parkinson disease, including 30 with homozygous parkin mutations, 114 with heterozygous parkin mutations, and 287 noncarriers, Alcalay et al. (2012) found no association between carrying a parkin mutation and increased risk of cancer, as determined by self-reporting. In a review of the literature on parkin as a tumor suppressor gene, Alcalay et al. (2012) noted that the 6q26 region may be prone to instability and deletion, even among those without cancer; evidence of point mutations in cancer cell lines may be misleading; and the function of parkin as an E3 ligase is not sufficient to confer tumor suppressor activity.
Parkinson Disease
In a Japanese patient with autosomal recessive juvenile Parkinson disease (600116) (Matsumine et al., 1997), Kitada et al. (1998) identified a deletion of 5 exons (exons 3-7) in the PARK2 gene (602544.0001). Four other PDJ patients from 3 unrelated families had a deletion affecting exon 4 alone (602544.0002).
Abbas et al. (1999) analyzed the 12 coding exons of the parkin gene in 35 mostly European families with early-onset autosomal recessive parkinsonism. In 1 family, a homozygous deletion of exon 4 could be detected. By direct sequencing of the exons in the index patients of the remaining 34 families, 8 previously undescribed point mutations (homozygous or heterozygous) (see, e.g., W453X, 602544.0007 and K161N, 602544.0008) were detected in 8 families that included 20 patients. The mutations segregated with the disease and were not detected on control chromosomes. Four mutations (3 frameshifts and 1 nonsense mutation) caused truncation of the parkin protein; the other 4 were missense mutations that probably affect amino acids that are important to the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. In many patients, the phenotype was indistinguishable from that of idiopathic Parkinson disease.
Autosomal recessive juvenile parkinsonism due to deletions and mutations in the parkin gene is associated with degeneration of pigmented neurons in the substantia nigra, similar to that seen in Parkinson disease, but Lewy bodies are not observed. Farrer et al. (2001) reported studies of 2 American families with a novel mutation of the parkin gene and multigenerational dystonia and parkinsonism. Although no genealogic link between the 2 families was identified (one was of Irish and the other of German descent), a common 6q25.2-q27 haplotype was found. A 40-bp deletion in exon 3 of the parkin gene segregated with the disease on this haplotype. One individual was a compound heterozygote for this deletion and a 924C-T transition predicting an R275W amino acid substitution (602544.0017). This patient, who had onset of symptoms at age 41 years and died in a traffic accident at age 52, was found to have Lewy bodies in the brain at autopsy. This led Farrer et al. (2001) to suggest that parkin mutations may confer increased susceptibility to typical idiopathic Parkinson disease (PD; 168600).
West et al. (2002) reported that a single-nucleotide polymorphism within the parkin core promoter, -258T/G, is located in a region of DNA that binds nuclear protein from human substantia nigra in vitro, and functionally affects gene transcription. In a population-based series of 296 PD cases and 184 controls, the -258G allele was associated with idiopathic PD (odds ratio 1.52, p less than 0.05).
In 270 unrelated patients of mixed ethnic background with dopa-responsive parkinsonism, including 64 cases of early onset (age of onset less than 50 years) with a family history, 174 cases of early onset with no family history, and 32 cases of late onset with a family history, Kock et al. (2002) found parkin mutations in 31 (18%) of 173 screened early-onset patients.
In 2 of 65 unrelated patients with early-onset parkinsonism, Klein et al. (2005) identified the respective R275W and K211N (602544.0018) mutations in the parkin gene.
In a case-control study involving 386 Chinese individuals with Parkinson disease and 367 controls, Tan et al. (2005) found that the parkin promoter -258G variant was associated with an increased risk of sporadic PD in individuals over 65 years of age (OR, 1.83; p less than 0.004). Tan et al. (2005) demonstrated that the transcriptional activity of -258T was significantly higher than -258G, and the difference was further increased under conditions of oxidative stress.
Sriram et al. (2005) investigated 12 missense and nonsense point mutations (see, e.g., T240R, Q311X, W453X, K161N, and R275W) in parkin for E3 ligase activity, localization, and ability to bind, ubiquitinate, and affect the degradation of 2 substrates, synphilin-1 and tRNA synthetase cofactor p38 (JTV1; 600859). Parkin mutants varied by intracellular localization, binding to substrates and enzymatic activity, yet they were ultimately deficient in the ability to degrade substrate. Sriram et al. (2005) suggested that not all parkin mutations may result in loss of parkin E3 ligase activity, but all mutations appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity, or targeting of proteins to the proteasome for degradation.
Kay et al. (2007) found that heterozygous parkin mutations were as common in 301 controls as in 302 PD patients, and they replicated the finding in an independent set of 1,260 PD patients and 1,657 controls. Thirty-four variants, including 21 novel variants, were identified. Kay et al. (2007) concluded that heterozygous mutations in the parkin gene are not likely to contribute to the development of Parkinson disease. Quantitative gene dosage was not examined.
Lesage et al. (2008) identified homozygous or compound heterozygous mutations in the PARK2 gene in 13 of 172 French patients with early-onset PD. Five additional patients in the cohort had exon deletions or duplications with unknown parental phase. Thirteen patients had heterozygous PARK2 mutations, 4 of whom carried the R275W mutation. Although those with heterozygous mutations had early disease onset at an average of 38 years, this was still later compared to those with 2 mutations (24.2 years).
Choi et al. (2008) identified mutations in the PARK2 gene in 4 of 72 unrelated Korean patients with onset of PD before age 50. Two patients had biallelic mutations, and 2 had heterozygous mutations.
Mortiboys et al. (2008) found that fibroblasts derived from PD patients with biallelic mutations in the PARK2 gene had significantly decreased mitochondrial complex I activity and ATP production compared to controls. Patient fibroblasts also showed altered morphology, including a greater degree of mitochondrial branching, as well as increased susceptibility to mitochondrial toxins. Complete knockdown of parkin using siRNA in control fibroblasts confirmed that the effects were due to parkin deficiency. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in humans, did not result in impaired mitochondrial function or morphology. Treatment with experimental neuroprotective glutathione replacement compounds resulted in restoration of the mitochondrial membrane potential.
Using primary dermal fibroblasts originating from PD patients with various PINK1 (608309) mutations, Rakovic et al. (2010) showed that PINK1 regulates the stress-induced decrease of endogenous parkin (PARK2); that mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of parkin; that endogenous PINK1 is stabilized on depolarized mitochondria; and that mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of parkin and its mitochondrial translocation. Depolarizing or nondepolarizing stressors led to the same effect on detectable parkin levels and its mitochondrial targeting. Although this effect on parkin was independent of the mitochondrial membrane potential, Rakovic et al. (2010) demonstrated a differential effect of depolarizing versus nondepolarizing stressors on endogenous levels of PINK1. The study of Rakovic et al. (2010) demonstrated the effect of an environmental factor, stress, on the interaction of PINK1 and parkin in mutants versus controls.
Gene Dosage and Parkinson Disease
Hedrich et al. (2001) found alterations of parkin gene dosage in 7 of 21 patients with Parkinson disease (average age of onset 40 years). Mutations included heterozygous and compound heterozygous deletions of exons 2, 3, 5, and 7; homozygous deletion of exon 7; and heterozygous duplications of exon 4. Two patients carried more than 2 parkin mutations. The authors suggested that gene dosage studies may afford a higher yield of mutation detection than conventional mutational screening. Hedrich et al. (2002) performed mutation analysis and gene dosage studies of the parkin gene in 50 patients with onset of PD under the age of 50 years and from various ethnic backgrounds. They identified 17 different parkin mutations, including 8 previously unreported mutations, and 6 different gene dosage alterations. Among the 50 probands, they found compound heterozygous mutations in 14%, heterozygous mutations in 12%, and no parkin mutation in 74%.
Oliveri et al. (2001) investigated the role of the parkin gene in 118 patients who had onset of PD after age 45 years: 23 patients with familial autosomal recessive PD and 95 patients with sporadic PD. No mutations in the parkin gene were detected in either group of patients and there were no differences between patients and controls in the allele and genotype frequencies of 4 exonic parkin polymorphisms. Oliveri et al. (2001) concluded that the parkin gene is not involved in the pathogenesis of classic late-onset PD. Kann et al. (2002) noted that gene dosage alterations play an important role in parkin-related parkinsonism, and commented that Oliveri et al. (2001) did not perform quantitative PCR gene dosage experiments in their study of patients with late-onset PD.
Kann et al. (2002) screened 111 community-based early-onset (age of onset less than 50 years) parkinsonism patients from Germany for mutations in the parkin gene. The overall mutation rate was 9.0%, comprising 3.6% compound heterozygotes (2 or 3 mutations) and 5.4% heterozygotes (single mutations). Thus, gene dosage alterations accounted for 67% of all mutations. There was a tendency toward decreased age at onset, increased prevalence of dystonia, and positive family history with increased number of parkin mutations.
Wu et al. (2005) identified PARK2 mutations in 4 of 41 Taiwanese probands with early-onset PD. Three patients had heterozygous mutations.
In both sporadic patients with Parkinson disease and healthy controls, Tan et al. (2005) identified a variant of parkin with deletion of exon 4 (see 602544.0002), which the authors referred to as a 'splice variant.' Expression analysis showed that PD patients had significantly increased expression of the splice variant relative to wildtype parkin compared to control individuals. In addition, the ratio of the splice variant to wildtype parkin increased with age in PD patients, but not in controls. Tan et al. (2005) postulated that increased expression of the PARK2 splice variant lacking exon 4 may predispose to disease development.
To examine the effects of heterozygous mutations in the PRKN gene on the risk of Parkinson disease, Zhu et al. (2022) examined 2 large cohorts: an NIH Parkinson disease control cohort with whole-exome screening data, and the UK Biobank cohort with whole-exome sequencing and genotyping array data. Using the NIH cohort, the authors validated genotyping array screening for the detection of patients with biallelic PRKN mutations. Functional assays performed on patients from the NIH cohort were able to rule out second cryptic variants in patients with one heterozygous pathogenic mutation. Using the UK Biobank data, they found that 1.8% of participants had 1 pathogenic PRKN variant and 1/7800 participants had biallelic variants. Those with 1 PRKN pathologic variant were equally as likely as noncarriers to have Parkinson disease or a parent with Parkinson disease, providing evidence that heterozygosity for pathogenic PRKN mutations does not increase the risk of Parkinson disease.
Trinh et al. (2023) investigated mitochondrial DNA heteroplasmy in whole blood in patients with PD and biallelic mutations in the PINK1 (608309) or PRKN gene, patients with PD and heterozygous mutations in PINK1 or PRKN, patients with biallelic or heteroplasmic mutations in PINK1 or PRKN but without PD, patients with idiopathic PD, and control individuals. Individuals with PD and biallelic mutations in PINK1 or PRKN had significantly more mtDNA heteroplasmy compared to patients with PD and heterozygous mutations in PINK1 or PRKN or controls. Regardless of affected or unaffected status for PD, individuals with biallelic mutations in PINK1 or PRKN had significantly more mtDNA heteroplasmy compared to individuals with heterozygous mutations in PINK1 or PRKN. Patients with PD and heterozygous mutations in PINK1 or PRKN had more heteroplasmy compared to individuals without PD and heterozygous mutations in PINK1 or PRKN, or patients with idiopathic PD. Heteroplasmy load was also found to correlate to IL6 (147620) levels in PINK1 or PRKN mutation carriers, possibly demonstrating a link between mtDNA integrity and inflammation. Trinh et al. (2023) concluded that PINK1 and PRKN mutations contribute to somatic mtDNA heteroplasmy in a dose-dependent manner.
Susceptibility to Leprosy
Using a positional cloning strategy in 197 Vietnamese leprosy simplex families (i.e., families with 2 unaffected parents and 1 affected child), Mira et al. (2004) found significant associations between leprosy (see 607572) and 17 markers in the 5-prime regulatory region shared by PARK2 and PACRG. Possession of 2 or more of the 17 risk alleles was highly predictive of leprosy, particularly the SNP markers denoted PARK2_e01(-2599) and rs1040079, with P values calculated using genomic controls (Devlin and Roeder, 1999). Mira et al. (2004) confirmed these results in 587 Brazilian leprosy cases and 388 unaffected controls. RT-PCR analysis detected wide expression of both PARK2 and PACRG in tissues, including immune tissues, and suggested that, in addition to the common bidirectional promoter, gene-specific transcriptional activators may be involved in regulating cell- and tissue-specific gene expression. In addition, PARK2, and to a lesser extent, PACRG, were found to be expressed in Schwann cells and macrophages, the primary host cells of Mycobacterium leprae, the causative agent of leprosy. Mira et al. (2004) noted that both genes are linked to the ubiquitin-mediated proteolysis system, which heretofore has received little attention in the study of leprosy pathogenesis and the control of M. leprae in the human host.
Malhotra et al. (2006) studied an ethnically homogeneous population of Indian leprosy patients and controls for associations with SNPs in the common regulatory region of PARK2 and PACRG. After Bonferroni corrections, they found no significant associations, in contrast with the findings in Vietnamese and Brazilian populations reported by Mira et al. (2004). Malhotra et al. (2006) concluded that risks associated with these SNPs vary in different populations.
Using multivariate analysis, Alter et al. (2013) replicated the findings of Mira et al. (2004) showing a susceptibility locus in the shared PARK2 and PACRG promoter region in a Vietnamese population. They also found that 2 of the SNPs, rs1333955 and rs2023004, were associated with susceptibility to leprosy in a northern Indian population. The populations varied in terms of linkage disequilibrium, possibly explaining differences in univariate analysis between the 2 populations. There was also a stronger association in younger patients in the 2 populations.
Susceptibility to Cancer
Cesari et al. (2003) found 2 somatic truncating deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian cancers (167000). Somatic homozygous deletions of exon 2 of the PARK2 gene (602544.0015) were found in 2 lung adenocarcinoma (see 211980 and 608935) cell lines, Calu-3 and H-1573. The findings suggested that PARK2 may act as a tumor suppressor gene. An Editorial Expression of Concern was published regarding the article by Cesari et al. (2003).
Veeriah et al. (2010) provided evidence that PARK2 acts as a tumor suppressor gene in glioblastoma multiforme (GBM; see 137800), colon cancer (114500), and lung cancer. Microarray analysis detected copy number loss of PARK2 in 53 (24.5%) of 216 glioblastomas and in 24 (24.4%) of 98 colon cancers. Both homozygous and heterozygous loss was observed; heterozygous loss was more common. Among 242 human cancers, different somatic point mutations in the PARK2 gene were found in 7 GBM specimens, 4 lung cancers, and 2 colon cancer cells lines. These somatic mutations occurred in the same domains as germline PD mutations, including the UBL domain, the RING finger domain, and the in-between RING fingers domain (IBR). In vitro functional studies in tumor cell lines showed that tumor growth was greater in cells with mutant PARK2, that wildtype PARK2 decreased tumor growth in vivo, and that mutant PARK2 caused decreased E3 ligase function and decreased interaction with and regulation of cyclin E (123837). These changes can promote tumor cell growth.
Among 73 families with early-onset Parkinson disease (before age 45 years), Lucking et al. (2000) found that 36 (49%) had PARK2 mutations. Age at onset ranged from 7 to 58 years. Among 100 patients with isolated early-onset Parkinson disease, mutations were detected in 10 of 13 patients (77%) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3%) with an age at onset of more than 30 years. Nineteen different exon rearrangements and 16 different point mutations were identified. The mean age at onset in the patients with PARK2 mutations was younger than in those without mutations (32 +/- 11 vs 42 +/- 11 years; P less than 0.001), and they were more likely to have symmetric involvement and dystonia at onset, hyperreflexia at onset or later, a good response to levodopa therapy, and levodopa-induced dyskinesias during treatment. Lucking et al. (2000) commented that molecular studies are necessary to make an accurate diagnosis in many of these cases; the diagnosis cannot be based only on the clinical manifestations.
Foroud et al. (2003) identified 25 different parkin mutations in 103 affected individuals from 47 families with PD, including 41 individuals with mutations in both alleles and 62 individuals with a single mutation in only 1 allele. Individuals with 2 parkin mutations had an earlier age at disease onset and longer disease duration than those with 1 mutation. Thirty-five subjects (35%) with a parkin mutation had an age at onset of 60 years or above, with 30 of these 35 having only 1 mutant allele. The authors concluded that mutations in the parkin gene occur among individuals with PD with an older age at onset (greater than 60 years) who have a positive family history of the disease.
In 16 of 307 (5%) families with PD, Oliveira et al. (2003) identified mutations in the parkin gene, which included 18% of all early-onset and 2% of all late-onset families. Three families were homozygous, 3 families were compound heterozygous, and in 10 families, all the patients had heterozygous mutations. The results showed that mutations in exon 7 were observed primarily in heterozygous PD patients with a later age at onset. Oliveira et al. (2003) concluded that mutations in the parkin gene contribute to the common form of PD, and that heterozygous mutations act as susceptibility alleles for the late-onset form of PD.
Poorkaj et al. (2004) undertook a study to determine whether patients with early-onset PD should be screened for parkin mutations as part of their clinical workup. Patients with a diagnosis of PD and onset at or before 40 years of age were selected for genotyping by sequence and dosage analysis for all 12 exons. Mutations were found in 7 of 39 patients. Two of these were compound heterozygous; 5 were heterozygous. Early-onset PD accounted for 10% of PD patients, and 18% of the early-onset patients had parkin mutations. Assuming a strictly recessive inheritance, only 5% of early-onset cases had a pathogenic parkin genotype. The remaining 13% were heterozygous, and whether heterozygous parkin mutations were the cause of early-onset PD in these patients was unclear.
Pramstaller et al. (2005) provided detailed clinical and molecular follow-up of a large kindred from a remote village in the Western Alps of South Tyrol in northern Italy affected with adult-onset Parkinson disease inherited in an autosomal dominant pattern. The family was originally reported by Klein et al. (2000). The clinical features were indistinguishable from idiopathic Parkinson disease, and none of the patients demonstrated typical features of PARK2. The mean age at onset was 52.8 years, but ranged from 20 to 76 years. Five of 25 definitely affected individuals were found to be compound heterozygous for 2 deletions in the PARK2 gene (602544.0010 and 602544.0019); 8 patients had only 1 of these deletions; the mutational status of 5 deceased patients was unknown; and 7 patients had no PARK2 mutations. Patients who were compound heterozygous had earlier onset than those with heterozygous mutations. Pramstaller et al. (2005) concluded that heterozygous mutations in the PARK2 gene contribute to idiopathic PD.
Sun et al. (2006) identified PARK2 mutations in 23 (12.6%) of 183 unrelated probands from families with PD. The families were selected for affected sibs sharing 2 alleles at the PARK2 locus or 1 or more family members with onset before age 54 years. Sun et al. (2006) identified 18 different mutations in the PARK2 gene, including 4 novel mutations. Ten (43%) families had compound heterozygous mutations, 3 (13%) had homozygous mutations, and 10 (43%) had heterozygous mutations. Patients with heterozygous mutations had disease onset 11.7 years earlier compared to PD patients with no PARK2 mutations, whereas patients with 2 or more PARK2 mutations had disease onset 13.2 years earlier compared to patients with 1 mutation. Sun et al. (2006) concluded that heterozygous PARK2 mutations significantly influence the age at onset of PD.
Clark et al. (2006) identified pathogenic PARK2 mutations in 10 (9.9%) of 101 patients with early-onset PD. One patient was homozygous, and 9 were heterozygous. Pathogenic heterozygous mutations were not identified in 105 control individuals. The findings lent further evidence to the hypothesis that heterozygous PARK2 mutations may increase susceptibility to early-onset PD.
Using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, Periquet et al. (2001) performed haplotype analysis in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations, and each mutation was detected in more than 1 family. The results supported the hypothesis that exon rearrangements occurred independently and recurrently, whereas some point mutations, found in families from different geographic origins, may have been transmitted from a common founder.
Lincoln et al. (2003) reported 6 probands with possible or probable early-onset Parkinson disease (onset before 45 years) with a 40-bp deletion in exon 3 of the PARK2 gene. Five patients reported a family history of the disease. Haplotype analysis indicated that the deletion was likely a founder mutation, most probably of Irish descent. The authors commented on the phenotypic variability.
Bakija-Konsuo et al. (2011) found that the frequencies of 2 regulatory polymorphisms in the PARK2 and PACRG promoter region, rs1040079 and rs9356058, differed in 2 isolated Croatian island populations, Mljet and Rab. Mljet, near Dubrovnik, was the site of a medieval leprosarium established under a quarantine policy, whereas Rab, in the north, has no record of leprosy patients. There was a significantly higher frequency of allele C of rs9356058 and also an increase in allele A of rs1040079 in the Mljet population compared with the Rab population. Bakija-Konsuo et al. (2011) proposed that the increased frequency of the protective alleles in the Mljet population may be due to positive selection as a result of exposure to leprosy.
Itier et al. (2003) showed that inactivation of the parkin gene in mice resulted in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release, and inhibition of glutamate neurotransmission. The levels of dopamine were increased in the limbic brain areas of parkin mutant mice, and there was a shift towards increased metabolism of dopamine by monoamine oxidase. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals. Glutathione levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death.
Lorenzetti et al. (2004) showed that the mouse mutant 'quaking (viable)' (qkv) results from deletion of approximately 1 megabase on mouse chromosome 17. The mouse homologs of the human parkin gene and the human parkin coregulated gene (PACRG) are contained entirely within the deletion breakpoints. The deletion results in complete lack of expression of the parkin gene product. The authors found, however, that the deletion of parkin in the brains of the mutant mice did not result in the loss of dopaminergic neurons typical of patients with autosomal recessive juvenile Parkinson disease. Also, alpha-synuclein (SNCA; 163890), a target of parkin-dependent ubiquitination, did not accumulate in the mutant brains.
By targeted deletion of exon 7 of the Park2 gene, von Coelln et al. (2004) generated parkin null mice. These mice showed a loss of catecholaminergic neurons in the locus ceruleus and an accompanying loss of norepinephrine in discrete regions of the central nervous system. Moreover, there was a dramatic reduction of the norepinephrine-dependent startle response. The nigrostriatal dopaminergic system did not show impairment.
Springer et al. (2005) identified and characterized the C. elegans parkin homolog pdr1. Pdr1 protein physically associated and cooperated with a conserved degradation machinery to mediate ubiquitin conjugation. In contrast to pdr1 loss-of-function mutants, an in-frame deletion (lg103) variant with altered solubility and intracellular localization properties was hypersensitive toward different proteotoxic stress conditions. Both ER-derived folding stress and cytosolic stress conferred by expression of mutant human alpha-synuclein resulted in severe developmental defects and lethality in pdr1 lg103-mutant background. The corresponding truncated protein aggregated in cell culture but still interacted with its ubiquitylation coenzymes. In contrast to other complete gene knockouts or RNAi models of parkin function, this C. elegans model recapitulated parkin insolubility and aggregation similar to several autosomal recessive juvenile parkinsonism (600116)-linked parkin mutations.
Using 2-dimensional gel electrophoresis and mass spectrometry, Palacino et al. (2004) identified 14 proteins that were altered in parkin -/- mouse brain lysates compared with wildtype mouse brain lysates. Eight of the 14 proteins were involved in either oxidative phosphorylation or antioxidant activities. Consistent with this finding, parkin -/- mice exhibited decreased oxidative phosphorylation, weight gain, and antioxidant capacity, as well as increased reactive oxygen species-mediated tissue damage. Palacino et al. (2004) concluded that parkin has essential roles in regulating normal respiratory function in mitochondria and in the protection of cells from oxidative stress.
Park et al. (2006) generated and characterized loss of function mutants of Drosophila Pink1 (608309) and observed that Pink1 mutants share marked phenotypic similarities with parkin mutants. They showed that Pink1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl2 (151430) demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of Pink1 mutants. Transgenic expression of parkin markedly ameliorated all Pink1 loss of function phenotypes, but not vice versa, suggesting that parkin functions downstream of PINK1. Taken together, Park et al. (2006) concluded that their genetic evidence clearly establishes that parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.
Clark et al. (2006) found that loss of Drosophila parkin results in phenotypes similar to those caused by loss of Pink1 function. Removal of Drosophila Pink1 function resulted in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology, and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in Pink1 mutants. Expression of human PINK1 in the Drosophila testes restored male fertility and normal mitochondrial morphology in a portion of Pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Overexpression of parkin rescued the male sterility and mitochondrial morphology defects of Pink1 mutants, whereas double mutants removing both Pink1 and parkin function showed muscle phenotypes identical to those observed in either mutant alone. Clark et al. (2006) concluded that Pink1 and parkin function, at least in part, in the same pathway, with Pink1 functioning upstream of parkin. The role of the Pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson disease pathogenesis.
Yang et al. (2006) found that inactivation of Pink1 in Drosophila using RNAi resulted in abnormal wing posture, energy depletion, selective muscle degeneration, and shortened life span. The muscle degeneration was preceded by mitochondrial enlargement and disintegration. In addition, inactivation of Pink1 resulted in the degeneration of dopaminergic neurons in the brain. The level of parkin was significantly reduced in Pink1 RNAi flies compared to controls, and overexpression of human parkin was able to rescue most of the defects caused by Pink1 inactivation. The findings suggested that parkin and Pink1 interact in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.
In Drosophila, Poole et al. (2008) provided evidence that parkin acts downstream of Pink1 in a linear pathway. Overexpression of parkin was able to rescue muscle defects of Pink1 mutants, but not vice versa. Heterozygous mutations in Drp1 (DNM1L; 603850), a key component of mitochondrial fission, enhanced Pink1 and parkin mutant phenotypes and were largely lethal. In contrast, increased Drp1 gene dosage or mutations affecting the mitochondrial fusion-promoting components Opa1 (605290) and Mfn2 (608507) suppressed the Pink1 and parkin mutant phenotypes. The findings suggested that the Pink1/parkin pathway promotes mitochondrial fission and that loss of activity of either gene results in decreased fission and impaired tissue integrity.
Fujiwara et al. (2008) found that 48-week-old parkin-null mice had reduced body weight and increased liver weight compared to wildtype, but no obvious neurologic abnormalities. At 72 and 96 weeks, parkin-null mouse liver showed enhanced hepatocyte proliferation and macroscopic hepatic tumors with characteristics of hepatocellular carcinoma, including expression of alpha-fetoprotein (AFP; 104150). Microarray analysis of parkin-null mouse liver revealed altered gene expression profiles, including endogenous follistatin (FST; 136470), which was commonly upregulated in both nontumorous and tumorous liver tissue. Parkin deficiency resulted in suppression of caspase activation and rendered hepatocytes resistant to apoptosis in a follistatin-dependent manner, suggesting that parkin deficiency results in follistatin upregulation. The findings were consistent with the hypothesis that parkin is a tumor suppressor gene.
Kim et al. (2012) found that overexpression of the Gsto1a isoform of Drosophila Gsto1 (605482) partially reversed the phenotype of parkin mutant flies. Gsto1a and mitochondrial ATPase synthase levels were reduced in parkin mutant flies. Overexpression of Gsto1 restored mitochondrial ATPase synthase assembly and activity via glutathionylation of the ATPase beta subunit (ATP5B; 102910). Knockdown of Atp5b in flies via RNA interference induced some of the parkin mutant phenotype, including muscle degeneration and cellular accumulation of tubulin (see 602529). Double mutation of parkin and Gsto1a accentuated the phenotype of parkin mutant flies, with dramatically enhanced degeneration of indirect flight muscles. Kim et al. (2012) concluded that Drosophila Gsto1 plays a protective role in parkin mutants by regulating mitochondrial ATP synthase activity.
Kubli et al. (2013) found that, although parkin -/- mouse hearts had disorganized mitochondrial networks and significantly smaller mitochondria, they showed normal cardiac and mitochondrial function. However, parkin -/- mice were more sensitive to myocardial infarction than wildtype mice. Parkin -/- mice developed larger infarcts and had reduced survival, with reduced mitophagy accompanied by accumulation of swollen, dysfunctional mitochondria after the infarction.
Sul et al. (2013) found that Faf1 expression accumulated in the ventral midbrain of parkin -/- and MPTP-treated PD model mice and was elevated in parkin -/- mouse embryonic fibroblasts. Knockdown of Faf1 via gene trap insertion into Faf1 intron 8 generated a hypomorphic allele (gt) that protected Faf1 gt/gt mice from MPTP-induced dopaminergic neuronal loss. Faf1 gt/gt mice were also protected from locomotor defects found in MPTP-treated PD model mice. Sul et al. (2013) noted that FAF1 is upregulated in PD patients, and they hypothesized that FAF1 may contribute to PD through deregulation of ubiquitin-mediated protein degradation.
Sliter et al. (2018) reported a strong inflammatory phenotype in both parkin-null and Pink1-null (608309) mice following exhaustive exercise, and in Prkn-null;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA). Inflammation resulting from either exhaustive exercise or mtDNA mutation was completely rescued by concurrent loss of Sting (612374), a central regulator of the type I interferon response to cytosolic DNA. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn-null;mutator mice were also rescued by loss of Sting, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also displayed elevated cytokines. Sliter et al. (2018) concluded that their results supported a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity.
By positional cloning in a Japanese patient with a microdeletion involving marker D6S305, which is closely linked to autosomal recessive juvenile parkinsonism (PARK2; 600116), Kitada et al. (1998) isolated a gene whose protein product they designated 'parkin.' By PCR amplification, Kitada et al. (1998) demonstrated that the patient lacked exons 3-7 of the parkin gene.
In 4 patients with autosomal recessive juvenile parkinsonism (PARK2; 600116) from 3 unrelated families, Kitada et al. (1998) demonstrated a deletion affecting only exon 4 of the parkin gene.
In affected members of a family with juvenile-onset parkinsonism originally reported by Ishikawa and Miyatake (1995), Hayashi et al. (2000) identified a homozygous deletion of exon 4 of the PARK2 gene. Some of the patients showed dystonia, including torticollis.
Jeon et al. (2001) identified homozygosity for the exon 4 mutation in the PARK2 gene in a Korean woman with juvenile Parkinson disease. She had bradykinesia, postural imbalance, and tremor since the age of 12, striatal dopaminergic dysfunction as shown by PET scan, and favorable response to L-DOPA therapy. The patient's mother and brother were healthy and did not have the mutation; her father, who had died at age 40 from injuries sustained in an automobile accident, was reportedly healthy at the time of the accident.
In both sporadic patients with Parkinson disease and healthy controls, Tan et al. (2005) identified a variant of parkin with deletion of exon 4, which the authors referred to as a 'splice variant.' Expression analysis showed that PD patients had significantly increased expression of the splice variant relative to wildtype parkin compared to control individuals. In addition, the ratio of the splice variant to wildtype parkin increased with age in PD patients, but not in controls. Tan et al. (2005) postulated that increased expression of the PARK2 splice variant lacking exon 4 may predispose to disease development.
In a Turkish family, Hattori et al. (1998) found a thr240-to-arg (T240R) mutation in the parkin gene in a 17-year-old girl with juvenile Parkinson disease (PARK2; 600116). She presented with bradykinesia, rigidity, and tremor at rest and in posture. The age of onset was 13 years. Her parents were first-degree relatives.
Sriram et al. (2005) showed that the T240R mutation results in complete loss-of-function with completely abolished binding and ubiquitination activity of parkin.
In a 38-year-old Turkish woman with PDJ (600116), who presented with tremor and bradykinesia on the right side at the age of 35 years (PARK2; 600116), Hattori et al. (1998) found a gln311-to-ter (Q311X) mutation in the parkin gene. The patient had no sibs and her parents were first-degree relatives. Marked sleep benefit (diurnal fluctuation) and hyperreflexia in the lower limbs was found in this patient as well as in the other Turkish patient reported by Hattori et al. (1998); see 602544.0003.
Sriram et al. (2005) showed that the Q311X mutation is 'ligase dead' because of its inability to catalyze ubiquitination of self and substrates (synphilin-1 and JTV1).
To determine the frequency of deletions in the PARK2 gene, Lucking et al. (1998) searched for homozygous deletions in the PARK2 gene in 12 PARK2-linked families with autosomal recessive juvenile parkinsonism (600116) and known or suspected consanguinity (a total of 32 patients). Five of the families originated from Italy, 4 from France, 1 from the Netherlands, 1 from Portugal, and 1 from Algeria. Six of the families had previously been reported by Tassin et al. (1998). They found 2 novel homozygous deletions in 8 patients from 3 families. The Algerian family carried a deletion of exons 8 and 9 (602544.0006). Deletions of exon 3 were found in 1 French and 1 Portuguese family. Deletions in the PARK2 gene accounted, therefore, for only a quarter of the PARK2-linked families with known or suspected consanguinity, which suggested that point mutations may be more prominent. Mean age at onset and clinical severity were similar in the deleted and nondeleted families. The overall clinical features were also similar, except that patients with exon 3 deletions had significantly lower frequencies of tremor than the nondeleted patients, a significantly later mean age at onset than those with exon 8-9 deletions, and a trend toward greater severity for similar disease durations. Both deletions were expected to cause frameshifts introducing a premature stop codon and resulting in truncated proteins with probable loss of function. The exon 3 deletion might have more harmful effects, leading to a shorter truncated protein, since these patients were more severely affected. The exon 8-9 deletion was, however, associated with earlier age at onset, as if the less truncated protein resulted in an additional toxic effect.
To determine the frequency of deletions in the PARK2 gene, Lucking et al. (1998) searched for homozygous deletions in the PARK2 gene in 12 PARK2-linked families with autosomal recessive juvenile parkinsonism (600116) and known or suspected consanguinity (a total of 32 patients). Five of the families originated from Italy, 4 from France, 1 from the Netherlands, 1 from Portugal, and 1 from Algeria. Six of the families had previously been reported by Tassin et al. (1998). They found 2 novel homozygous deletions in 8 patients from 3 families. The Algerian family carried a deletion of exons 8 and 9. Deletions of exon 3 (602544.0005) were found in 1 French and 1 Portuguese family. Deletions in the PARK2 gene accounted, therefore, for only a quarter of the PARK2-linked families with known or suspected consanguinity, which suggested that point mutations may be more prominent. Mean age at onset and clinical severity were similar in the deleted and nondeleted families. The overall clinical features were also similar, except that patients with exon 3 deletions had significantly lower frequencies of tremor than the nondeleted patients, a significantly later mean age at onset than those with exon 8-9 deletions, and a trend toward greater severity for similar disease durations. Both deletions were expected to cause frameshifts introducing a premature stop codon and resulting in truncated proteins with probable loss of function. The exon 3 deletion might have more harmful effects, leading to a shorter truncated protein, since these patients were more severely affected. The exon 8-9 deletion was, however, associated with earlier age at onset, as if the less truncated protein resulted in an additional toxic effect.
Of 8 novel mutations identified in the PARK2 gene in European families with autosomal recessive juvenile parkinsonism (600116) by Abbas et al. (1999), 1 was a nonsense mutation, trp453 to ter (W453X).
Sriram et al. (2005) showed that the W453X mutation retains the ability to autoubiquitinate but not the ability to ubiquitinate substrate (synphilin-1 and JTV1) and is largely defective in binding to substrate.
Of 8 novel mutations identified in the PARK2 gene in European families with autosomal recessive juvenile parkinsonism (600116) by Abbas et al. (1999), 1 of the 4 missense mutations was lys161 to asn (K161N).
Sriram et al. (2005) showed that the K161N mutation results in complete loss-of-function with completely abolished binding and ubiquitination activity of parkin.
In 4 affected brothers from a sibship of 10 in an Arabic Muslim Israeli family segregating Parkinson disease (600116), Nisipeanu et al. (2001) found homozygosity for deletion of 1 adenine at nucleotide 202 in exon 2 of the PARK2 gene. The mutation led to a frameshift and premature termination 8 amino acid residues downstream. Ages at onset were 35, 33, 37, and 30 years, and the disease duration 27, 22, 9, and 14 years. The parkinsonian symptomatology was similar in all. Hand tremor was the first symptom; later, bradykinesia and rigidity were observed. In addition to the rest tremor, all presented postural hand tremor. None had orthostatic hypotension, urinary dysfunction, constipation, sleep benefit, or diurnal variation. Response to levodopa therapy was excellent and the total daily dose remained low for a long period.
Inzelberg et al. (2003) identified another branch of the family reported by Nisipeanu et al. (2001) in which 2 first cousins carried the same homozygous 202delA mutation in the PARK2 gene. Both patients had early-onset parkinsonism (onset at ages 19 and 23), with the additional feature of truncal dystonia. One developed camptocormia with severe trunk flexion (up to 90 degrees), and the other had axial dystonia and scoliosis. The authors noted the phenotypic heterogeneity of the mutation.
In a man with onset of Parkinson disease (600116) at age 38 years, Hedrich et al. (2001) found homozygosity for 2 mutations: deletion of exon 7 as well as a C-to-A transversion at nucleotide 346 in exon 3, resulting in an ala82-to-glu substitution (602544.0011).
In 4 male sibs with Parkinson disease, Klein et al. (2000) and Pramstaller et al. (2005) identified compound heterozygosity for 2 deletions in the PARK2 gene: a deletion of exon 7 and a 1-bp deletion (1072delT) in exon 9 (602544.0019). The family was a large 7-generation kindred that originated from South Tyrol in northern Italy. Among a total of 25 family members with PD, 4 were heterozygous for the exon 7 deletion, and 4 were heterozygous for 1072delT. Pramstaller et al. (2005) concluded that heterozygous mutations in the PARK2 gene contribute to late-onset PD.
For discussion of the C-to-A transversion at nucleotide 346 in exon 3 of the PARK2 gene, resulting in an ala82-to-glu (A82E) substitution, that was found in compound heterozygous state in a patient with Parkinson disease (PARK2; 600116) by Hedrich et al. (2001), see 602544.0010.
In affected members of 2 Colombian families with juvenile Parkinson disease (600116), Pineda-Trujillo et al. (2001) identified a homozygous 736G-A transition in exon 6 of the PARK2 gene, resulting in a cys212-to-tyr (C212Y) substitution.
Hoenicka et al. (2002) described a Spanish family in which 3 brothers who were compound heterozygotes for 2 mutations in the PARK2 gene, C212Y and val56 to glu (V56E; 602544.0013), developed Parkinson disease at ages 33, 33, and 27 years. The father, who was a heterozygous carrier of only the C212Y mutation, developed clinical symptoms of Parkinson disease at age 78 years.
For discussion of the val56-to-glu (V56E) substitution in the PARK2 gene that was found in compound heterozygous state in affected members of a Spanish family with Parkinson disease (PARK2; 600116) by Hoenicka et al. (2002), see (602544.0012).
In 2 Spanish families, Hoenicka et al. (2002) found deletion of 1 adenine at nucleotide 202 of the PARK2 gene in members with juvenile Parkinson disease (600116). The mutation was homozygous in 1 family and compound heterozygous with a deletion of exons 8 and 9 (602544.0006) in the other. In the first family, there was 1 individual who was a heterozygous carrier of only the 255delA mutation who developed transient drug-induced parkinsonism at 45 years of age while being treated with haloperidol.
The 255delA mutation in PARK2 was originally described by Abbas et al. (1999).
In 2 lung adenocarcinoma (see 211980 and 608935) cell lines, Calu-3 and H-1573, Cesari et al. (2003) found homozygous deletion of exon 2 of the PARK2 gene. An Editorial Expression of Concern was published regarding the article by Cesari et al. (2003).
In 3 of 20 ovarian adenocarcinomas (167000), Cesari et al. (2003) found 2 truncating deletions in the PARK2 gene. The findings suggested that PARK2 may be a tumor suppressor gene. An Editorial Expression of Concern was published regarding the article by Cesari et al. (2003).
In 2 of 65 unrelated Italian patients with autosomal recessive early-onset parkinsonism (600116), Klein et al. (2005) identified a 924C-T transition in exon 7 of the PARK2 gene, resulting in an arg275-to-trp (R275W) substitution. One patient was heterozygous for the R275W mutation, and the other patient was compound heterozygous for R275W and a 734A-T transversion in exon 6 of the PARK2 gene, resulting in a lys211-to-asn (K211N; 602544.0018) substitution.
Cookson et al. (2003) found that R275W parkin was distributed in large cytoplasmic and nuclear inclusions in transfected human embryonic kidney cells and in primary cultured neurons. Accumulation/colocalization with vimentin (VIM; 193060) indicated that the inclusion bodies were aggresomes, a cellular response to misfolded protein.
Sriram et al. (2005) showed that the R275W mutation results in reduced binding of substrate JTV1 (600859) but retained ubiquitination activity for self and substrates. They suggested that the R275W mutation could impair the ubiquitin-proteasome system through sequestration into aggresome-like structures in the cell and away from their site of normal function.
For discussion of the 734A-T transversion in exon 6 of the PARK2 gene, resulting in a lys211-to-asn (K211N) substitution, that was found in compound heterozygous state in an Italian patient with Parkinson disease (PARK2; 600116) by Klein et al. (2005), see 602544.0017.
In 4 male sibs with Parkinson disease (600116), Klein et al. (2000) and Pramstaller et al. (2005) identified compound heterozygosity for 2 deletions in the PARK2 gene: a 1-bp deletion (1072delT) in exon 9 and a deletion of exon 7 (602544.0010). The family was a large 7-generation kindred that originated from South Tyrol in northern Italy. The ages at onset were 31, 48, 49, 55, and 64 years, later than that usually observed for patients with PARK2 mutations. Among a total of 25 family members with PD, 4 were heterozygous for the exon 7 deletion, and 4 were heterozygous for 1072delT. Patients with heterozygous mutations showed an age at onset and clinical symptoms similar to idiopathic PD. Pramstaller et al. (2005) concluded that heterozygous mutations in the PARK2 gene contribute to late-onset PD.
In 10 affected members of a consanguineous Brazilian family with PARK2 (600116), Chien et al. (2006) identified a homozygous splice site mutation in intron 1 of the PARK2 gene. RT-PCR analysis showed absence of PARK2 mRNA, consistent with a loss-of-function mutation. The family was from an isolated region in northeastern Brazil, and their ancestors had originated from Portugal. One individual who was heterozygous for the splice site mutation developed neuroleptic-induced parkinsonism, suggesting that haploinsufficiency was a predisposing factor.
In 4 sibs with early-onset Parkinson disease (PARK2; 600116), Deng et al. (2006) identified compound heterozygosity for 2 mutations in the PARK2 gene: a C-to-T transition in exon 6, resulting in a thr240-to-met (T240M) substitution, and a deletion of exons 5 and 6 (602544.0022). The T240M substitution is predicted to eliminate a phosphorylation site for casein kinase II and occurs in the same codon as another reported PARK2 mutation T240R (602544.0003), indicating that this is an important functional residue. Heterozygosity for the T240M and exon 5-6 deletion was found in 5 and 10 unaffected family members, respectively, suggesting that heterozygosity for these mutations does not lead to disease. An unaffected 56-year-old sister of the affected sibs was also compound heterozygous for both mutations, suggesting incomplete penetrance.
For discussion of the deletion of exons 5 and 6 in the PARK2 gene that was found in compound heterozygous state in sibs with early-onset Parkinson disease (PARK2; 600116) by Deng et al. (2006), see 602544.0021.
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