Alternative titles; symbols
HGNC Approved Gene Symbol: SOD1
SNOMEDCT: 1201863001;
Cytogenetic location: 21q22.11 Genomic coordinates (GRCh38): 21:31,659,693-31,668,931 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.11 | Amyotrophic lateral sclerosis 1 | 105400 | Autosomal dominant; Autosomal recessive | 3 |
| Spastic tetraplegia and axial hypotonia, progressive | 618598 | Autosomal recessive | 3 |
The SOD1 gene encodes superoxide dismutase-1 (EC 1.15.1.1), a major cytoplasmic antioxidant enzyme that metabolizes superoxide radicals to molecular oxygen and hydrogen peroxide, thus providing a defense against oxygen toxicity (Niwa et al., 2007). Soluble cytoplasmic SOD1 is a copper- and zinc-containing enzyme; the SOD1 gene maps to chromosome 21q22 (Sherman et al., 1983). SOD2 (147460) is a distinct mitochondrial enzyme that contains manganese; the SOD2 gene maps to 6q25. SOD1 is a homodimer and SOD2 a tetramer (Beckman et al., 1973).
Fridovich (1979) concluded that SOD1 and SOD2 evolved from different primordial genes, which is an example of analogy, not homology, and of convergent evolution. Doonan et al. (1984) cited the superoxide dismutases as an example of cytosolic and mitochondrial isoenzymes with no apparent evolutionary relationship.
Barra et al. (1980) and Jabusch et al. (1980) independently determined the amino acid structure of human superoxide dismutase-1. The 153-residue protein shares approximately 82% homology with the bovine protein.
Sherman et al. (1983) isolated clones corresponding to the human SOD1 gene. The deduced 153-residue protein has a calculated molecular mass of approximately 18.5 kD. Two mRNA transcripts of 0.5 and 0.7 kb were detected. Both mRNAs encoded the same protein, which had functional activity in vitro.
By RT-PCR analysis, Hirano et al. (2000) identified 5 splice variants of SOD1. The variants were expressed in a tissue-specific manner, including expression in brain, a region involved in amyotrophic lateral sclerosis (ALS; 105400). Hirano et al. (2000) designated the variants, which were found in both ALS patients and controls, LP1 (lacking part of exon 1), LP1P2 (lacking part of exon 1 and part of exon 2), LE2 (lacking entire exon 2), LE2E3 (lacking entire exons 2 and 3), and LP1E2E3 (lacking part of exon 1 and entire exons 2 and 3).
Green et al. (2002) sequenced, characterized, and mapped the canine SOD1 gene. The deduced canine SOD1 protein contains 153 amino acids and shares more than 79% sequence identity with mammalian homologs.
By mouse-man somatic cell hybridization, Tan et al. (1973) mapped the SOD1 gene to chromosome 21.
Lin et al. (1980) demonstrated that the genes for soluble Sod1 and interferon sensitivity are syntenic in the mouse and located on mouse chromosome 16, which is homologous to part of human chromosome 21.
In the mouse, Novak et al. (1980) showed that a locus affecting SOD1 activity was closely linked to the H-2 cluster, suggesting that the locus may be regulatory in nature.
Wulfsberg et al. (1983) found normal levels of SOD1 in a patient with an interstitial deletion of chromosome 21 leading to monosomy for band q21. They concluded that the gene for SOD1 is located at 21q22.1.
Huret et al. (1987) used in situ hybridization on metaphase chromosomes to confirm SOD1 gene localization in the segment enclosing the distal part of chromosome 21q21 and 21q22.1.
Green et al. (2002) mapped the canine Sod1 gene to chromosome 31 close to syntenic group 13 on the radiation hybrid map in the vicinity of the sodium/myoinositol transporter (SMIT) gene (SLC5A3; 600444).
SOD1 Dosage Effect in Trisomy 21 (Down Syndrome)
Sichitiu et al. (1974) noted that the fact that SOD1 was elevated in trisomy 21, or Down syndrome (190685), added support to the location of the gene on chromosome 21.
Feaster et al. (1977) demonstrated dosage effects of SOD1 in nucleated lymphocytes and polymorphonuclear cells from persons with trisomy 21 and monosomy 21. Earlier studies had been done with anucleated erythrocytes and platelets. Kedziora et al. (1979) cast some doubt on the significance of excessive SOD1 in the Down syndrome phenotype, because SOD1 levels were normal in 3 patients with Down syndrome due to translocations.
Nakai et al. (1984) extended the observations on SOD1 dosage effect in aneuploid cells: a case of monosomy 21 showed half normal levels of enzyme.
Brooksbank and Balazs (1983) showed that SOD1 activity in trisomy 21 fetal brain was enhanced while glutathione peroxidase (see, e.g., GPX1, 138320) activity, which would have a compensating effect, was not. Cerebral cortex tissue from a patient with Down syndrome showed increased lipoperoxidation compared to controls. The authors suggested that increased SOD1 activity could result in an abnormally high concentration of hydrogen peroxide in nerve cells, which may cause free radical damage to cell membrane lipids and play a pathogenetic role in Down syndrome.
Huret et al. (1987) studied an 18-month-old boy with many typical Down syndrome features but a normal cytogenetic analysis. However, SOD1 was increased in the patient's red cells as in trisomy 21, and Southern blot analysis demonstrated that the patient had 3 SOD1 genes. In situ hybridization on metaphase chromosomes with the same probe confirmed the gene localization in the segment enclosing the distal part of chromosome 21q21 and 21q22.1. Huret et al. (1987) concluded were that the Down syndrome phenotype of this patient was due to microduplication of a segment of chromosome 21.
In a family with clinical features of Down syndrome caused by submicroscopic duplication of distal band q22.1 in addition to bands q22.2 and q22.3 of chromosome 21, Korenberg et al. (1990) found that the SOD1 and APP (104760) genes did not play a necessary role in generating the classic Down syndrome features.
Ackerman et al. (1988) described a young child with partial monosomy 21 in whom pulmonary oxygen toxicity occurred due presumably to deficiency of SOD1. The child underwent 2 operative procedures with different anesthetic techniques, which resulted in exposure to low concentrations of inspired oxygen during the first procedure and exposure to high concentrations during the second. Signs of pulmonary oxygen toxicity developed only after exposure to the high concentration. Blood samples obtained on 3 separate occasions showed levels of SOD1 that were 40% of those in controls.
Minc-Golomb et al. (1991) suggested that overexpression of the SOD1 gene is responsible for alteration in prostaglandin biosynthesis in trisomy 21 cells.
McCord and Fridovich (1969) demonstrated that superoxide dismutase catalyzes the oxidation/reduction conversion of superoxide radicals to molecular oxygen and hydrogen peroxide. The name 'superoxide dismutase' comes from the fact that the reaction is a 'dismutation' of superoxide anions. The protein had been known for over 30 years as a copper-containing, low molecular weight cytoplasmic protein identified in erythrocytes, referred to as 'erythrocuprein' or 'hemocuprein.' See review of Fridovich (1975).
Richardson et al. (1976) noted the similarity between the 3-dimensional protein structures of immunoglobulins and individual Cu-Zn SOD1 subunits.
Keller et al. (1991) concluded that SOD1 is a peroxisomal enzyme. On immunofluorescence using 4 monoclonal antibodies, SOD1 colocalized with catalase (CAT; 115500) in human fibroblasts and hepatoma cells. In fibroblasts from patients with Zellweger syndrome (see 214100), in which there are peroxisomal defects, SOD1 was not transported to the peroxisomal ghosts, but, like catalase, remained in the cytoplasm. A study of yeast cells expressing human SOD1 showed that the enzyme is translocated to peroxisomes. Crapo et al. (1992), however, concluded that SOD1 is widely distributed in the cell cytosol and in the cell nucleus, consistent with its being a soluble cytosolic protein. Mitochondria and secretory compartments did not label with the antibodies they used. In human cells, peroxisomes showed a labeling density slightly less than that of cytoplasm.
Using immunohistochemistry, Pardo et al. (1995) demonstrated SOD1 in motor neurons, interneurons, and sensory neurons of mouse and human spinal cord. SOD1 was distributed in a punctate pattern throughout neuronal perikarya, in proximal dendrites, and in terminal axons. In the brain, SOD1 was present in motor and sensory cranial nerve nuclei, as well as diffusely through the brain in the neurons of the cortex, certain regions of the hippocampus, and amygdala. The intracellular localization was primarily cytoplasmic, but also included nuclei and membranous organelles, presumably peroxisomes. Due to the diffuse and abundant SOD1 expression, Pardo et al. (1995) concluded that pathogenic SOD1 mutations result in a toxic gain of adverse function rather than haploinsufficiency.
Huang et al. (2000) reported that certain estrogen derivatives selectively kill human leukemia cells but not normal lymphocytes. Using cDNA microarray and biochemical approaches, Huang et al. (2000) identified SOD1 as a target of this drug action and showed that chemical modifications at the 2-carbon (2-OH, 2-OCH3) of the estrogen derivatives are essential for SOD inhibition and for induction of apoptosis. Inhibition of SOD causes accumulation of cellular superoxide radical and leads to free radical-mediated damage to mitochondrial membranes, the release of cytochrome c from mitochondria, and apoptosis of the cancer cells. Huang et al. (2000) concluded that targeting SOD1 may be a promising approach to the selective killing of cancer cells and that mechanism-based combinations of SOD inhibitors with free radical-producing agents may have clinical applications.
Growth factor signaling elicits an increase in reactive oxygen species, which inactivates protein tyrosine phosphatases (PTPs; see 176876) by oxidizing an active-site cysteine, shifting the balance within cells toward phosphorylation and allowing kinase cascades to propagate. Juarez et al. (2008) showed that chemical inhibition of SOD1 in human tumor and endothelial cells prevented formation of sufficiently high levels of H2O2, resulting in protection of PTPs from H2O2-mediated inactivation. This, in turn, led to inhibition of EGF (131530)-, IGF1 (147440)-, and FGF2 (134920)-mediated phosphorylation of ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and caused downregulation of PDGF receptor (PDGFRB; 173410). SOD1 inhibition increased the steady-state levels of superoxide, which induced protein oxidation in A431 human tumor cells but spared phosphatases. Thus, SOD1 inhibition in A431 cells resulted in both prooxidant effects caused by increased superoxide levels and antioxidant effects caused by reduced H2O2 levels. Juarez et al. (2008) concluded that SOD1 plays an essential role in growth factor-mediated MAPK signaling by mediating transient oxidation and inactivation of PTPs.
DeCroo et al. (1988) reported an isoelectric focusing technique to look for SOD1 heterogeneity in erythrocytes.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Amyotrophic Lateral Sclerosis 1
In patients from 13 different families with amyotrophic lateral sclerosis (ALS; 105400), Rosen et al. (1993) identified 11 different heterozygous mutations in the SOD1 gene (147450.0001-147450.0011). The authors presented 2 possible mechanisms by which mutations in SOD1 could cause the disorder: decreased SOD1 activity leading to the accumulation of toxic superoxide radicals, or increased SOD1 activity leading to excessive levels of hydrogen peroxide and a highly toxic hydroxyl radical, which can be formed through the reaction of hydrogen peroxide with a transition metal such as iron. Increased SOD1 activity may result in a dominant-negative effect.
In a complete screening of the SOD1 coding region in 25 families with ALS, Deng et al. (1993) found that the A4V (147450.0012) substitution in exon 1 was the most frequent, occurring in 8 families. Other mutations were identified in exons 2, 4, and 5, but not in the active site region formed by exon 3. Examination of the crystal structure of human SOD1 established that all 12 observed sites of mutation causing ALS alter conserved interactions critical to the beta-barrel fold and dimer contact, rather than catalysis. Red cells from heterozygotes had less than 50% normal SOD activity, consistent with a structurally defective SOD dimer.
In a review of familial amyotrophic lateral sclerosis, de Belleroche et al. (1995) cataloged 30 missense mutations and a 2-bp deletion in the SOD1 gene.
Orrell et al. (1997) described a mutation in exon 3 of the SOD1 gene (147450.0028) associated with familial ALS. Previously, more than 50 different mutations had been described involving exons 1, 2, 4, and 5.
Cudkowicz et al. (1997) registered 366 families in a study of dominantly inherited ALS. They screened 290 families for mutations in the SOD1 gene and detected mutations in 68 families. The A4V mutation was the most common, occurring in 50% of families.
Andersen et al. (1995) identified a homozygous mutation in the SOD1 gene (D90A; 147450.0015) in 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS. Several of the families were consanguineous, indicating autosomal recessive inheritance. In a worldwide haplotype study of 28 pedigrees with the D90A mutation, Al-Chalabi et al. (1998) found that 20 recessive families shared the same founder haplotype, regardless of geographic location, whereas several founders existed for the 8 dominant families. The findings confirmed that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation was recessive. Al-Chalabi et al. (1998) proposed that a tightly linked protective factor modifies the toxic effect of mutant SOD1 in recessive families.
In 2 sibs with ALS, Hand et al. (2001) identified compound heterozygosity in the SOD1 gene: D90A (147450.0015) and D96N (147450.0032), indicating autosomal recessive inheritance.
Aguirre et al. (1999) used a nonradioactive SSCP method, in combination with solid phase sequencing, to screen the entire SOD1 coding region and flanking intronic sequences for mutations in 23 patients from 11 ALS families and 69 patients with sporadic ALS, all of Belgian origin. In 7 families, 3 different mutations were identified: L38V (147450.0002), D90A, and G93C (147450.0007). The D90A mutation was found only in heterozygous state, in 2 families and in 1 apparently sporadic case.
Among 233 patients with sporadic ALS, Broom et al. (2004) found no association between disease susceptibility or phenotype and a deletion and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing against a major role for wildtype SOD1 in sporadic ALS.
Sato et al. (2005) measured the ratio of mutant-to-normal SOD1 protein in 29 ALS patients with mutations in the SOD1 gene. Although there was no relation to age at onset, turnover of mutant SOD1 was correlated with a shorter disease survival time.
Millecamps et al. (2010) identified 18 different SOD1 missense mutations in 20 (12.3%) of 162 French probands with familial ALS. Compared to those with ALS caused by mutations in other genes, those with SOD1 tended to have predominantly lower limb onset. One-third of SOD1 patients survived for more than 7 years: these patients had an earlier disease onset compared to those presenting with a more rapid course. No patients with SOD1 mutations developed cognitive impairment.
Studies on Mutant SOD1 Proteins
Lyons et al. (1996) observed that replacement of zinc ion in the zinc sites of mutant SOD1 proteins with either copper ion or cobalt ion yielded metal-substituted derivatives with spectroscopic properties different from those of the analogous derivative of the wildtype proteins. The findings indicated that the geometries of binding of these metal ions to the zinc site were affected by the mutations. Several of the ALS-associated mutant copper-zinc oxide dismutases were also found to be reduced by ascorbate at significantly greater rates than the wildtype proteins. Lyons et al. (1996) concluded that similar alterations in the properties of the zinc binding site can be caused by mutations scattered throughout the protein structure.
Estevez et al. (1999) observed that the loss of zinc from either wildtype or ALS-mutant SOD was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wildtype Cu,Zn SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Estevez et al. (1999) concluded that zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide.
Okado-Matsumoto and Fridovich (2002) demonstrated that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins block the uptake of familial ALS-associated mutant SOD1, while having no effect on wildtype SOD1. The binding of mutant SOD1 to heat shock proteins in the extract of neuroblastoma cells leads to formation of sedimentable aggregates. The authors suggested that this binding of heat shock proteins to mutant forms of a protein abundant in motor neurons, such as SOD1, makes heat shock proteins unavailable for their proper antiapoptotic functions and ultimately leads to motor neuron death. The hypothesis could explain a mechanism of a toxic gain of function.
Lindberg et al. (2002) looked for folding-related defects by comparing the unfolding behavior of 5 SOD1 mutants with distinct structural characteristics: A4V (147450.0012) at the interface between the N and C termini, C6F (147450.0020) in the hydrophobic core, D90A (147450.0015) at the protein surface, and G93A (147450.0008) and G93C (147450.0007), which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affected the stability of the native protein, yet all shared a pronounced destabilization of the metal-free apoprotein state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus, organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species.
Valentine and Hart (2003) reviewed the 2 hypotheses that had dominated discussion of the toxicity of mutant SOD1 proteins: the oligomerization and oxidative damage hypotheses. The oligomerization hypothesis maintained that mutant SOD1 proteins are, or become, misfolded and consequently oligomerize into increasingly high molecular mass species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintained that mutant SOD1 proteins catalyze oxidative reactions that damage substrates critical for viability of the altered cells. Valentine and Hart (2003) reviewed some of the properties of both wildtype and mutant SOD1 proteins and suggested how these properties may be relevant to the 2 hypotheses, which they proposed were not necessarily mutually exclusive.
Stathopulos et al. (2003) reported that purified SOD formed aggregates in vitro under destabilizing solution conditions by a process involving a transition from small amorphous species to fibrils. The assembly process and the tinctorial and structural properties of the in vitro aggregates resembled those for aggregates observed in vivo. Furthermore, Stathopulos et al. (2003) found that the familial ALS SOD1 mutations A4V (147450.0012), E100G (147450.0009), G93A (147450.0008), and G93R (147450.0033) decreased protein stability, which correlated with an increase in the propensity of the mutants to form aggregates. These mutations also increase the rate of protein unfolding. The data supported the hypothesis that the toxic gain of function for many different familial ALS-associated mutant SODs is a consequence of protein destabilization, which leads to an increase in the formation of cytotoxic protein aggregates.
Hough et al. (2004) stated that more than 90 point mutations in the SOD1 gene had been found to lead to the development of familial ALS. They pointed to evidence suggesting that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes.
Hough et al. (2004) determined the crystal structure of the A4V (147450.0012) and I113T (147450.0011) mutants to 1.9 and 1.6 angstroms, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the 2 monomers. This effect was also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data showed that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wildtype superoxide dismutase than was observed in the A4V crystal structure. The results demonstrated that the A4V and I113T mutants are substantially destabilized in comparison with wildtype SOD1. Commenting on the work of Hough et al. (2004), Ray and Lansbury (2004) raised the possibility of therapeutic measures to stabilize the SOD1 dimer. The general strategy of inhibiting potentially pathogenic aggregation by stabilizing native oligomers was first proposed and accomplished by Koo et al. (1999) in connection with another aggregation-dependent degenerative disease, familial amyloid polyneuropathy, which is caused by point mutation in the gene encoding transthyretin (TTR; 176300).
Miyazaki et al. (2004) found that NEDL1 (HECW1; 610384), a neuronal ubiquitin-protein ligase, bound translocon-associated protein-delta (TRAPD, or SSR4; 300090) and also bound and ubiquitinated mutant SOD1, but not wildtype SOD1. The strength of the interaction between NEDL1 and mutant SOD1 was proportional to the severity of the SOD1 mutation. NEDL1 associated with mutant SOD1 and ubiquitin in Lewy body-like hyaline inclusions in ventral horn motor neurons of familial ALS patients and mutant Sod1 transgenic mice. Yeast 2-hybrid screening identified dishevelled-1 (DVL1; 601365), a key transducer in the WNT (see WNT1, 164820) signaling pathway, as a physiologic substrate for NEDL1. Mutant SOD1 interacted with DVL1 in the presence of NEDL1 and caused DVL1 dysfunction.
Rodriguez et al. (2005) used differential scanning calorimetry and hydrogen-deuterium (H/D) exchange, followed by mass spectrometric analysis, to compare ALS-associated SOD1 mutants with wildtype SOD1. They found that the mutant proteins were not universally destabilized, and that several mutants had normal metallation properties and resembled the wildtype protein in terms of thermal stability and H/D kinetics. Rodriguez et al. (2005) concluded that the causes of SOD1-linked ALS are complex and are not simply related to apoprotein stability, although destabilization may contribute to the toxicity of some ALS-associated SOD1 mutants.
Harraz et al. (2008) demonstrated that SOD1 directly regulated cellular NOX2 (300481) production of reactive oxygen species by binding RAC1 (602048) and inhibiting RAC1 GTPase activity. Oxidation of RAC1 uncoupled SOD1 binding in a reversible fashion, suggesting a model of redox sensing. ALS-associated mutant SOD1 lacked the redox sensitivity, resulting in enhanced RAC1/NOX1 activation and increased production of reactive oxygen species in neuronal and glial cells, leading to cell death. Glial cell toxicity in cell culture was attenuated by apocynin, a NOX inhibitor, and ALS mice treated with apocynin showed increased life span. Harraz et al. (2008) concluded that certain SOD1 mutations exert a dominant-negative effect by interfering with normal SOD1/RAC1 interactions. The results also showed that SOD1 can act as a regulatory molecule in addition to its role as a catabolic enzyme.
Using buoyant-density centrifugation and protease studies, Vande Velde et al. (2008) demonstrated that mutant misfolded SOD1, particularly dismutase-inactive SOD1, was bound to cytoplasmic outer mitochondrial membranes in an alkali- and salt-resistant manner. Mutant SOD1 binding was selective for mitochondrial membranes and restricted to spinal cord tissue. Vande Velde et al. (2008) postulated that exposure to mitochondria of misfolded mutant SOD1 conformers could be mediated by tissue-selective cytoplasmic chaperones, components on the cytoplasmic face of spinal mitochondria, or misfolded SOD1 conformers unique to spinal cord and with an affinity for mitochondrial membranes.
Using mouse motor neurons and human embryonic kidney cells expressing SOD1 proteins with ALS-associated mutations (e.g., G93A), Nishitoh et al. (2008) showed that mutant SOD1 interacted with the C-terminal cytoplasmic region of DERL1 (608813), a component of the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery, and triggered ER stress through ERAD dysfunction. Mutant SOD1 induced formation of an Ire1 (ERN1; 604033)-Traf2 (601895)-Ask1 (MAP3K5; 602448) complex on the ER membrane of mouse motor neurons and activated Ask1 by triggering ER stress-induced Ire1 activation. Dissociation of mutant SOD1 from Derl1 protected motor neurons from mutant SOD1-induced cell death. Furthermore, deletion of Ask1 partially mitigated motor neuron loss in vitro and extended the life span of SOD1-mutant transgenic mice. Nishitoh et al. (2008) concluded that interaction of mutant SOD1 with DERL1 is crucial for disease progression in familial ALS.
Prudencio et al. (2009) used a large set of data from SOD1-associated ALS pedigrees to identify correlations between disease features and biochemical/biophysical properties of more than 30 different SOD1 mutations. All ALS-associated SOD1 mutations tested increased the inherent aggregation propensity of the protein with considerable variation in relative aggregation propensity between mutations. Variation in aggregation rates was not influenced by differences in known protein properties such as enzyme activity, protein thermostability, mutation position, or degree of change in protein charge. However, the majority of pedigrees in which patients exhibited reproducibly short disease durations were associated with mutations that showed a high inherent propensity to induce SOD1 aggregation.
Magrane et al. (2009) generated NSC34 murine motor neuronal cells expressing wildtype or mutant SOD1 containing a cleavable intermembrane space (IMS) targeting signal to directly investigate the pathogenic role of mutant SOD1 in mitochondria. Mitochondrially-targeted SOD1 localized to the IMS, where it was enzymatically active. Mutant IMS-targeted SOD1 caused neuronal toxicity under metabolic and oxidative stress conditions. Motor neurons expressing IMS-mutant SOD1 demonstrated neurite mitochondrial fragmentation and impaired mitochondrial dynamics. These defects were associated with impaired maintenance of neuritic processes. Magrane et al. (2009) concluded that mutant SOD1 localized in the IMS is sufficient to cause mitochondrial abnormalities and neuronal toxicity and contributes to ALS pathogenesis.
Pedrini et al. (2010) showed that the toxicity of mutant SOD1 relies on its spinal cord mitochondria-specific interaction with BCL2 (151430). Mutant SOD1 induced morphologic changes and compromised mitochondrial membrane integrity leading to the release of cytochrome c only in the presence of BCL2. In cells and in mouse and human spinal cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a conformational change in BCL2 that resulted in the exposure of its BH3 domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain failed to support mutant SOD1-mediated mitochondrial toxicity.
Ferri et al. (2010) exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and IMS, where Grx1 (GLRX; 600443) is localized, or in the mitochondrial matrix, where Grx2 (GLRX2; 606820) is localized, as a tool for restoring a correct redox environment and preventing aggregation of mutant SOD1 (G93A; 147450.0008). Overexpression of Grx1 increased the solubility of mutant SOD1 in the cytosol but did not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells or in immortalized motoneurons. Conversely, the overexpression of Grx2 increased the solubility of mutant SOD1 in mitochondria, interfered with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserved mitochondrial function and strongly protected neuronal cells from apoptosis. The authors concluded that the toxicity of mutant SOD1 primarily arises from mitochondrial dysfunction, and that rescue of mitochondrial damage may represent a therapeutic strategy.
Progressive Spastic Tetraplegia and Axial Hypotonia
In a 3-year-old girl, born of consanguineous Afghan parents, with progressive spastic tetraplegia and axial hypotonia (STAHP; 618598), Andersen et al. (2019) identified a homozygous frameshift loss-of-function mutation in the SOD1 gene (c.335dupG; 147450.0036). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was found in the heterozygous state in each unaffected parent. Patient cells showed absent SOD1 activity, and cells from the clinically unaffected heterozygous parents had about 50% residual activity. Presence of a mutant 13-kD protein was detected in cells from both the patient and parents. Patient fibroblasts showed impaired growth in 19% oxygen, indicating extreme oxygen sensitivity.
Simultaneously and independently, Park et al. (2019) identified the same homozygous loss-of-function mutation in the SOD1 gene (c.335dupG) in a 7-year-old boy, born of consanguineous Afghan parents, with STAHP. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. SOD1 activity was undetectable in patient cells, and clinically unaffected family members who were heterozygous for the mutation had about 50% residual SOD1 activity compared to controls.
In a 2-year-old girl with STAHP, Ezer et al. (2022) identified a homozygous 3-bp deletion in the SOD1 gene (147450.0037). The mutation was identified by trio whole-exome sequencing, and the parents were shown to be mutation carriers. SOD enzyme activity and protein expression were absent in patient erythrocytes and reduced to about 50% of control levels in her parents.
Associations Pending Confirmation
For discussion of a possible association between variation in the SOD1 gene and keratoconus, see KTCN1 (148300).
Brewer (1967) identified superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique. In addition to the appearance of blue bands marking the site of the isozymes under investigation, there were light or achromatic areas resulting from a protein that oxidized tetrazolium dyes in the presence of phenazine and light. Brewer (1967) detected this enzyme in several human tissues and referred to it as 'indophenol oxidase A' (IPO-A).
Brewer (1967) observed an electrophoretic variant of IPO-A, which he called 'Morenci,' in 3 generations of a family with presumed male-to-male transmission. Baur (cited by Baur and Schorr, 1969) observed an electrophoretic variant of tetrazolium oxidase in a Caucasian mother and 1 of 2 children. Welch and Mears (1972) found an unusually high frequency of a variant in one of the Orkney Islands. Beckman (1973) reported on the frequency of the 'Morenci' SOD1 enzyme variant in a population of northern Sweden.
Baur and Schorr (1969) reported a genetic polymorphism of red cell tetrazolium oxidase (Sod1) in the dog.
Epstein et al. (1987) created transgenic mice with increased activity of Sod1 and proposed this as a useful model for investigating the effects of increased SOD1 in Down syndrome.
Animal Models of Amyotrophic Lateral Sclerosis
Gurney et al. (1994) showed that overexpression of Sod1 in transgenic mice led to an apparently specific defect in distal motor neuron terminals of the tongue and hindlimbs, indicating that this gene selectively affects motor neurons.
In cultured rat lumbar spinal cord slices, Rothstein et al. (1994) observed that chronic inhibition of Sod1 resulted in the apoptotic degeneration of spinal cord neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. Motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by a non-NMDA glutamate receptor antagonist. The findings suggested that loss of motor neurons in familial ALS may result from decreased SOD1 activity and may possibly be potentiated by inefficient glutamate transport.
In experiments that McCabe (1995) referred to as 'modeling Lou Gehrig's disease in the fruit fly,' Phillips et al. (1995) demonstrated that mutations in the Sod1 gene resulted in striking neuropathology in Drosophila. Heterozygotes with 1 wildtype and 1 deleted Sod allele retained the expected 50% of normal activity for this dimeric enzyme. However, heterozygotes with 1 wildtype and 1 missense Sod allele showed decreased Sod activities, ranging from 37% for a heterozygote carrying a missense mutation predicted from structural models to destabilize the dimer interface to an average of 13% for several heterozygotes carrying missense mutations predicted to destabilize the subunit fold. Genetic and biochemical evidence suggested a model of dimer disequilibrium whereby SOD activity in missense heterozygotes is reduced through entrapment of wildtype subunits into unstable or enzymatically inactive heterodimers.
In mice, Bruijn et al. (1998) found that neither a 6-fold increase in wildtype Sod1 nor its complete elimination affected the accumulated levels of mutant Sod1(G85R) protein. Thus, despite a decreased stability of Sod1(G85R) relative to wildtype Sod1 in the transgenic mice, the wildtype protein did not stabilize mutant Sod1. Moreover, the presence of Sod1(G85R) had no effect on the level or the activity of wildtype Sod1. Both elimination and elevation of wildtype Sod1 had no effect on mutant-mediated disease, which demonstrated that use of SOD mimetics is unlikely to be an effective therapy. The findings raised the question of whether toxicity arises from superoxide-mediated oxidative stress. Bruijn et al. (1998) demonstrated that aggregates containing SOD1 were common to disease caused by different mutants, implying that coaggregation of an unidentified essential component or components, or aberrant catalysis by misfolded mutants may underlie mutant-mediated toxicity.
Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. In transgenic mice with disruption of the gene encoding the major neurofilament subunit required for filament assembly (NEFL; 162280), Williamson et al. (1998) found that onset and progression of the disease caused by the familial ALS-associated Sod1 mutant G85R were significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons was reduced. In Nefl-deleted animals, levels of the 2 remaining neurofilament subunits, Nefm (162250) and Nefh (162230), were markedly reduced in axons but elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments were essential for Sod1-mediated disease, the absence of assembled neurofilaments both diminished selective vulnerability and slowed Sod1(G85R) mutant-mediated toxicity to motor neurons.
Nguyen et al. (2001) observed a correlation between Cdk5 (123831) activity and the longevity of transgenic mice with differing expression levels of the G37R mutant Sod1. Nguyen et al. (2001) bred the G37R transgene onto neurofilament mutant backgrounds and observed that the absence of NEFL provoked an accumulation of unassembled neurofilament subunits in the perikaryon of motor neurons and extended the average life span of the mutant mice.
In mice, Pasinelli et al. (2000) confirmed that activation of caspase-1 (CASP1; 147678) is an early event in the mechanism of toxicity from Sod1 mutants. However, neuronal death followed only after months of chronic caspase-1 activation, concomitantly with activation of caspase-3 (CASP3; 600636), the final step in the toxic cascade. Thus, the toxicity of mutant SOD1 is a sequential activation of at least 2 caspases, a chronic initiator and a final effector of cell death.
Kunst et al. (2000) studied the mouse model of ALS generated by Ripps et al. (1995) using a G86R mutation that corresponds to the human G85R mutation. Expression of the ALS phenotype in mice carrying this mutation was highly dependent upon the mouse genetic background, which is similar to the phenotypic variation observed in ALS patients carrying identical SOD1 mutations. In 1 background, mice developed an ALS phenotype at approximately 100 days. However, when these mice were bred into a mixed background, the onset was delayed (143 days to more than 2 years). Using 129 polymorphic autosomal markers in a genomewide scan, Kunst et al. (2000) identified a major genetic modifier locus with a maximum lod score of 5.07 on mouse chromosome 13. This 5- to 8-cM interval contains the spinal muscular atrophy (SMA)-associated gene Smn (600354) and 7 copies of the Naip gene (600355), suggesting a potential link between SMA and ALS.
Oeda et al. (2001) generated transgenic C. elegans strains containing wildtype and mutant human A4V (147450.0012), G37R (147450.0001), and G93A (147450.0008) SOD1 recombinant plasmids. The transgenic strains expressing mutant human SOD1 showed greater vulnerability to oxidative stress induced by 0.2 mM paraquat than a control that contained the wildtype human SOD1. In the absence of oxidative stress, mutant human SOD1 proteins were degraded more rapidly than the wildtype human SOD1 protein in C. elegans. In the presence of oxidative stress, however, this rapid degradation was inhibited, and the transgenic C. elegans coexpressing mutant human SOD1 demonstrated discrete aggregates in muscle tissue. These results suggested that oxidative damage inhibits the degradation of familial ALS-associated SOD1 mutant proteins, resulting in an aberrant accumulation of mutant proteins that might contribute to cytotoxicity.
By gene expression profiling in the diseased spinal cord of G93A transgenic mice, Olsen et al. (2001) found extensive astrocytic and microglial activation, as indicated by increased levels of GFAP (137780) and vimentin (193060), among others. There was also an increase in APOE (107741), perhaps reflecting myelin degeneration in peripheral nerves and consequent lipid turnover. This was followed by activation of genes involved in metal ion regulation, which the authors suggested represents a protective homeostatic response to limit metal-catalyzed free radical oxidative damage.
In murine cells, Raoul et al. (2002) showed that Fas (134637) triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase (600289). ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (602457)/caspase-8 (601763) cell death pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing ALS-linked SOD1 mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell death pathways may contribute to motor neuron loss in ALS.
Howland et al. (2002) created a transgenic rat model of ALS. Transgenic overexpression of the SOD1 gene harboring the G93A mutation resulted in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression. Disease onset was early, and progression was rapid thereafter, with affected rats reaching end stage on average within 11 days. Pathologic abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate receptor (SLC1A2; 600300) in the ventral horn of the spinal cord coincided with gliosis but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS.
Subramaniam et al. (2002) bred Ccs (603864) heterozygotes to Sod1 heterozygotes to generate double-knockout mice. Motor neurons in Ccs -/- mice showed increased rate of death after facial nerve axotomy, a response documented for Sod1 -/- mice. Thus, CCS is necessary for the efficient incorporation of copper into SOD1 in motor neurons. Although the absence of Ccs led to a significant reduction in the amount of copper-loaded mutant Sod1, it did not modify the onset and progression of motor neuron disease in Sod1-mutant mice. Subramaniam et al. (2002) concluded that CCS-dependent copper loading of mutant SOD1 plays no role in the pathogenesis of motor neuron disease in these mouse models.
Mattiazzi et al. (2002) examined mitochondria from transgenic mice expressing wildtype and G93A mutated human SOD1. They found that a significant proportion of enzymatically active SOD1 was localized in the intermembrane space of mitochondria. Presymptomatic G93A transgenic mice did not show significant mitochondrial abnormalities. Upon onset of disease, however, mitochondrial respiration, electron transfer, and ATP synthesis were disrupted. There was also oxidative damage to mitochondrial proteins and lipids.
Kirby et al. (2002) investigated alterations in gene expression by transfecting the murine motor neuronal cell line NSC34 with normal or mutant Cu/Zn SOD constructs. Presence of the mutant Cu/Zn SOD led to a decrease in expression of KIF3B (603754), a kinesin-like protein, which forms part of the KIF3 molecular motor. c-Fes (190030), thought to be involved in intracellular vesicle transport, was also decreased, further implicating the involvement of vesicular trafficking as a mode of action for mutant Cu/Zn SOD. In addition, a decrease was confirmed in ICAM1 (147840), a response in part due to the increased expression of SOD1, and decreased Bag1 (601497) expression was confirmed in 2 of 3 mutant cell lines, providing further support for the involvement of apoptosis in SOD1-associated motor neuron death.
Allen et al. (2003) determined that expression of human SOD1 carrying the G93A or G37R substitution in mouse motor neuron cultures resulted in the differential expression and altered function of proteins that regulate nitric oxide metabolism, intracellular redox conditions, and protein degradation. There was also significantly reduced total GST (see 134660) activity and significantly reduced activity of several proteasome enzymes.
Clement et al. (2003) found that in chimeric mice that are mixtures of normal and SOD1 mutant-expressing cells, toxicity to motor neurons required damage from mutant SOD1 acting within nonneuronal cells. Normal motor neurons in SOD1 mutant chimeras developed aspects of ALS pathology. Most important, nonneuronal cells that did not express mutant SOD1 delayed degeneration and significantly extended survival of mutant-expressing motor neurons.
Guo et al. (2003) generated transgenic mice overexpressing the glutamate transported EAAT2 and crossed these with mice bearing the ALS-associated SOD1 mutant G93A (147450.0008). The amount of EAAT2 protein and the associated Na(+)-dependent glutamate uptake was increased about 2-fold in EAAT2 transgenic mice. The transgenic EAAT2 protein was properly localized to the cell surface on the plasma membrane. Increased EAAT2 expression protected neurons from L-glutamate-induced cytotoxicity and cell death in vitro. The EAAT2/G93A double transgenic mice showed a statistically significant delay in grip strength decline but not in the onset of paralysis, body weight decline, or life span when compared with G93A littermates. A delay in the loss of motor neurons and their axonal morphologies, as well as other events including caspase-3 activation and SOD1 aggregation, were also observed. The authors hypothesized that loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.
Wang et al. (2003) demonstrated motor neuron disease in transgenic mice expressing a SOD1 variant that mutates the 4 histidine residues (e.g., H46R, 147450.0013) that coordinately bind copper. The accumulation of detergent-insoluble forms of SOD1 included full-length SOD1 proteins, peptide fragments, stable oligomers, and ubiquitinated entities. Moreover, chaperones Hsp25 (HSPB1; 602195) and alpha-B-crystallin (CRYAB; 123590) specifically cofractionated with insoluble SOD1. Expression of recombinant peptide fragments of wildtype SOD1 in cultured cells also produced insoluble species, suggesting that SOD1 possesses elements with an intrinsic propensity to aggregate.
Mitochondrial dysfunction, occurring not only in motor neurons but also in skeletal muscle, may play a critical role in the pathogenesis of ALS. In this regard, the life expectancy of transgenic mice carrying the human G93A mutation in the SOD1 gene is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state (Desport et al., 2001). These findings led Dupuis et al. (2004) to explore whether alterations in energy homeostasis may contribute to the disease process. In 2 strains of transgenic ALS mice, those with the G86R mutation in murine Sod1 or the G93A mutation in human SOD1, the authors showed important variations in a number of metabolic indicators, indicating a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. Dupuis et al. (2004) suggested that hypermetabolism, mainly of muscular origin, may represent by itself an additional driving force involved in increasing motor neuron vulnerability.
Using various immunoprecipitation and crosslinking experiments, Pasinelli et al. (2004) demonstrated that both wildtype and mutant SOD1 (G93A) interacted directly with the antiapoptotic protein BCL2 (151430) in both mouse and human spinal cord. The authors also found that BCL2 bound to mutant SOD1-containing aggregates in spinal cord mitochondria from both ALS mice (G93A) and an ALS patient with the A4V mutation (147450.0012). These aggregates were not identified in liver mitochondria, suggesting that spinal cord neurons are particularly susceptible to mutant SOD1. Pasinelli et al. (2004) suggested that entrapment of BCL2 by mutant SOD1 aggregates may deplete motor neurons of this antiapoptotic protein, resulting in decreased cell survival.
Liu et al. (2004) found that multiple disease-causing SOD1 mutants, including G37R (147450.0001), G85R (147450.0006), G93A (147450.0008), and H46R (147450.0013), but not wildtype SOD1, were imported selectively into the mitochondria of mouse spinal cord neurons, but not in unaffected tissues such as skeletal muscle and liver. The G37R SOD1 mutant was uniquely associated with brain mitochondria. The SOD1 mutants and covalently modified adducts of them accumulated as protein aggregates within the mitochondria. Similar findings were seen in spinal cord tissue from a patient with ALS caused by a SOD1 mutation. The findings were independent of the copper chaperone for SOD1 and dismutase activity of the specific mutations. Liu et al. (2004) concluded that the universal association of SOD1 mutants with mitochondria selectively in affected tissues represents a common property of these mutants that generates a cascade of damage to the motor neuron.
Wang et al. (2005) found that in L126X (147450.0026)-transgenic mice detergent-insoluble mutant protein specifically accumulated in somatodendritic compartments. Soluble forms of the mutant protein were undetectable in spinal cord at any age and the levels of accumulated protein directly correlated with disease symptoms. In vitro, alpha-B-crystallin suppressed aggregation of mutant SOD1. In vivo, alpha-B-crystallin immunoreactivity was most abundant in oligodendrocytes and upregulated in astrocytes of symptomatic mice; neither of these cell types accumulated mutant SOD1 immunoreactivity. Wang et al. (2005) suggested that damage to motor neuron cell bodies and dendrites within the spinal cord may be sufficient to induce motor neuron disease, and that activities of chaperones may modulate the cellular specificity of mutant SOD1 accumulation.
Perrin et al. (2005) analyzed gene expression in motor neurons during disease progression in transgenic SOD1-G93A mice that developed motor neuron loss. Only a small number of genes were differentially expressed in motor neurons at a presymptomatic age (27 out of 34,000 transcripts). There was an early specific upregulation of the gene coding for vimentin (193060) that was increased even further during disease progression. Vimentin expression was not only elevated in motor neurons, but the protein formed inclusions in motor neuron cytoplasm. Time-course analysis of motor neurons at a symptomatic age (90 and 120 days) showed a modest deregulation of only a few genes associated with cell death pathways; however, a massive upregulation of genes involved in cell growth and/or maintenance was observed.
Ferri et al. (2006) found that 12 different mutant SOD1 proteins associated with the mitochondria in mouse motoneuron cells to a greater extent than did wildtype SOD1 protein. Mutant SOD1 proteins tended to form crosslinked oligomers, and their presence caused a shift in the mitochondrial redox state, resulting in impairment of respiratory complex function. Further studies suggested that oxidative modification of SOD1 cysteine residues was involved in the toxic phenotype.
In transgenic mice with mutations in the SOD1 gene, Deng et al. (2006) found that overexpression of wildtype human SOD1 not only hastened the onset of the ALS phenotype, but also converted an unaffected phenotype to an ALS phenotype. Development of the ALS phenotype was associated with conversion of the wildtype SOD1 from a soluble to an aggregated form in the presence of mutant SOD1. The conversion was observed in mitochondria of the spinal cord and involved formation of insoluble SOD1 dimers and multimers that were cross-linked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. The findings provided further evidence of links among oxidation, protein aggregation, mitochondrial damage, and ALS. In an accompanying paper, the same group (Furukawa et al., 2006) found that a significant fraction of the insoluble SOD1 aggregates in spinal cord of ALS mice contained disulfide cross-linked SOD1 multimers. These multimers were found only in mitochondria from the spinal cord of symptomatic mice and not in unaffected tissues such as brain cortex or liver.
Using mice carrying a deletable mutant Sod1 gene, Boillee et al. (2006) demonstrated that expression within motor neurons is a primary determinant of ALS disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early phase but sharply slowed later disease progression. Boillee et al. (2006) concluded that onset and progression thus represent distinct ALS disease phases defined by mutant action within different cell types to generate non-cell autonomous killing of motor neurons, and that their findings validate therapies, including cell replacement, targeted to the nonneuronal cells.
In mice, Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage within muscles was not a significant contributor to non-cell autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression.
Using a specific antibody that detects SOD1 conformations in which the native dimer is disrupted or misfolded, Rakhit et al. (2007) established the presence of small amounts of misfolded SOD1 within degenerating motor neurons in the spinal cord from ALS mouse models with the human G37R, G85R, and G93A SOD1 mutations. Misfolded SOD1 was found primarily associated within the ventral horn and ventral roots in both mitochondrial and cytosolic cell fractions. Misfolded SOD1 appeared before the onset of symptoms and decreased at end-stage disease, concomitant with motor neuron loss.
In murine neuroblastoma cells, Niwa et al. (2007) found that nonphysiologic intermolecular disulfide bonds involving cys6 and cys111 of mutant SOD1 were important for high molecular weight aggregate formation, ubiquitylation, and neurotoxicity. Aggregation was decreased when these residues were replaced with serine. Dorfin (607119) ubiquitylated mutant SOD1 by recognizing the cys6 and cys111-disulfide cross-linked form and targeted it for proteasomal degradation.
Marden et al. (2007) evaluated the effects of NADPH oxidase-1 (NOX1; 300225) or Nox2 (CYBB; 300481) deletion on transgenic mice overexpressing human SOD1 with the ALS-associated G93A mutation by monitoring the onset and progression of disease using various indices. Disruption of either Nox1 or Nox2 significantly delayed progression of motor neuron disease in these mice. However, 50% survival rates were enhanced significantly more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased survival rates, suggesting that in the setting of random X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a substantial therapeutic benefit in ALS mice. Marden et al. (2007) concluded that NOX1 and NOX2 contribute to the progression of ALS.
Awano et al. (2009) found that canine degenerative myelopathy, a spontaneously occurring adult-onset neurodegenerative disease, was highly associated with a homozygous glu40-to-lys (E40K) mutation in the canine Sod1 gene. The mutation was found in affected breeds including the Pembroke Welsh corgi, boxer, Rhodesian ridgeback, Chesapeake Bay retriever, and German shepherd. The disorder was characterized clinically by adult onset of spasticity and proprioceptive ataxia, followed by weakness, paraplegia, and hyporeflexia. Histopathologic examination of the spinal cord of 46 affected dogs showed white matter degeneration with axonal and myelin loss and cytoplasmic Sod1-positive inclusions in surviving neurons. The disorder closely resembled human ALS.
Tateno et al. (2009) demonstrated that, starting from the pre-onset stage of ALS, misfolded SOD1 species associated specifically with Kap3 (KIFAP3; 601836) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargoes including choline acetyltransferase (CHAT; 118490). Motor axons in SOD1G93A-Tg mice also showed a reduction in CHAT transport from the pre-onset stage. Using a purified hybrid mouse neuroblastoma/rat glioma cell line NG108-15 transfected with SOD1 mutations, the authors showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species and that impairment was normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in spinal motor neurons from human ALS patients as well. Tateno et al. (2009) suggested that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of CHAT transport play a role in the pathophysiology of ALS.
In familial and sporadic ALS and in rodent models of the disease, alterations in the ubiquitin-proteasome system (UPS) may be responsible for the accumulation of potentially harmful ubiquitinated proteins, leading to motor neuron death. In the spinal cord of G93A-mutant SOD1 transgenic mice, Cheroni et al. (2009) found a decrease in constitutive proteasome subunits during disease progression. An increased immunoproteasome expression was also observed, which correlated with a local inflammatory response. These findings support the existence of proteasome modifications in ALS-vulnerable tissues. The authors crossed SOD1-G93A mice with transgenic mice expressing a fluorescently-tagged reporter substrate of the UPS. In double-transgenic UbG76V-GFP/SOD1-G93A mice, an increase in UbG76V-GFP reporter, indicative of UPS impairment, was detectable in a few spinal motor neurons and not in reactive astrocytes or microglia. The levels of reporter transcript were unaltered, suggesting that the accumulation of UbG76V-GFP was due to deficient reporter degradation. In some motor neurons the increase of UbG76V-GFP was accompanied by the accumulation of ubiquitin and phosphorylated neurofilaments, both markers of ALS pathology. Cheroni et al. (2009) suggested that UPS impairment occurs in motor neurons of mutant SOD1-linked ALS mice and may play a role in the disease progression.
Wang et al. (2009) studied the effect of wildtype SOD1 overexpression (WTSOD1) in a G85R (147450.0006) transgenic mouse model. The G85R/WTSOD1 double-transgenic mice had an acceleration of disease onset and shortened survival compared with mice carrying the G85R mutation alone. In addition, there was an earlier appearance of pathologic and immunohistochemical abnormalities. The spinal cord insoluble fraction from G85R/WTSOD1 mice had evidence of G85R/WTSOD1 heterodimers and WTSOD1 homodimers (in addition to G85R homodimers) with intermolecular disulfide bond crosslinking. Wang et al. (2009) suggested that wildtype SOD1 may be recruited into disease-associated aggregates by redox processes, providing an explanation for the accelerated disease seen in G85R/WTSOD1 double-transgenic mice following WTSOD1 overexpression, and suggested the importance of incorrect disulfide-linked protein in mutant SOD1 toxicity.
Karch et al. (2009) found that 3 transgenic mouse strains with Sod1 mutations developed accumulation of disulfide crosslinked, detergent-insoluble, Sod1 aggregates in the spinal cord that occurred primarily in the later stage of disease, concurrent with rapid progression. Although the mutant protein lacking normal intramolecular disulfide bonds was a major component of the insoluble SOD1 aggregates, the presence of aberrant intermolecular disulfide bonds did not appear to play a role in promoting Sod1 aggregation. Disulfide crosslinking was likely a secondary event to mutant Sod1 proteins coming into close proximity and forming high molecular weight structures. In addition, the majority of mutant Sod1 was consistent with reduced Sod1. Karch et al. (2009) proposed a model in which soluble forms of mutant SOD1 initiate disease, with larger aggregates resulting from abnormalities in the oxidation of intramolecular disulfide bonds only during the final stages of disease.
Wong and Martin (2010) created transgenic mice expressing wildtype, G37R (147450.0001), and G93A (147450.0008) human SOD1, only in skeletal muscle. These mice developed age-related neurologic and pathologic phenotypes consistent with ALS. Affected mice showed limb weakness and paresis with motor deficits. Skeletal muscles developed severe pathology involving oxidative damage, protein nitration, myofiber cell death, and marked neuromuscular junction abnormalities. Spinal motor neurons developed distal axonopathy, formed ubiquitinated inclusions, and degenerated through an apoptotic-like pathway involving caspase-3 (600636). Mice expressing wildtype and mutant forms of SOD1 developed motor neuron pathology. The authors concluded that SOD1 in skeletal muscle has a causal role in ALS, and they proposed a nonautonomous mechanism to explain the degeneration and selective vulnerability of these motor neurons.
Blacher et al. (2019) showed that ALS-prone Sod1 transgenic mice have a presymptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. Blacher et al. (2019) correlated 11 distinct commensal bacteria with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1 transgenic mice they demonstrated that Akkermansia muciniphila (AM) ameliorates, whereas Ruminococcus torques and Parabacteroides distasonis exacerbate, the symptoms of ALS. Furthermore, Sod1 transgenic mice that are administered AM accumulated AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improved motor symptoms and gene expression patterns in the spinal cord of Sod1 transgenic mice. In humans, Blacher et al. (2019) identified distinct microbiome and metabolite configurations, including reduced levels of nicotinamide systemically and in the CSF, in a small preliminary study that compared patients with ALS with household controls. Blacher et al. (2019) suggested that environmentally driven microbiome-brain interactions may modulate ALS in mice, and called for similar investigations in the human form of the disease.
Therapeutic Strategies in Animal Models of ALS
Kostic et al. (1997) found that overexpression of the protooncogene Bcl2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the familial ALS-linked SOD1 mutation G93A. However, the duration of the disease was unaltered. Overexpression of Bcl2 also attenuated the magnitude of spinal cord motor neuron degeneration in the familial ALS-transgenic mice. The studies suggested a role for gene intervention, with the use of Bcl2 or antiapoptotic Bcl2 homologs as potential therapies for ALS.
Cleveland (1999) reviewed the pathways then known or suggested for disease mechanism in SOD1-related ALS, diagrammed these pathways, and summarized potential therapies in his Figure 3. He pointed out that the best pharmacologic intervention to that time was the simple addition of creatine to the drinking water of Sod1G93A mice. Long used by athletes hoping to enhance energy reserves in muscle, creatine yielded a dose-dependent extension in survival of this ALS-modeling mouse, peaking at just under 4 weeks. How creatine provided this benefit mechanistically was unclear, but its availability at local health food stores made it 'a safe bet that it is already being taken widely.'
In transgenic mice expressing human G93A SOD1, Li et al. (2000) found that intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, prolonged life span by 22%. Moreover, zVAD-fmk was found to inhibit caspase-1 (147678) activity as well as caspase-1 and caspase-3 (600636) mRNA upregulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Li et al. (2000) found that caspases play an instrumental role in neurodegeneration in transgenic Sod1G93A mice, suggesting that caspase inhibition may have a protective role in ALS. Li et al. (2000) also demonstrated that zVAD-fmk decreased IL1-beta (147720), an indication that caspase-1 activity was inhibited.
Azzouz et al. (2000) injected the spinal cords of transgenic mice with a G93A SOD1 mutation with a recombinant adeno-associated virus (rAAV) encoding the antiapoptotic protein Bcl2. Injection resulted in sustained Bcl2 expression in motor neurons and significantly increased the number of surviving motor neurons at the end-stage of disease. Local Bcl2 expression in spinal motor neurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of mice harboring this mutation.
Friedlander (2003) discussed apoptosis and caspases in neurodegenerative diseases. They noted clinical trials of an inhibitor of apoptosis (minocycline) for neurodegenerative disorders (Fink et al., 1999; Chen et al., 2000). Zhang et al. (2003) reported that a combination of minocycline and creatine in ALS mice with the Sod1G93A mutation resulted in additive neuroprotection, delaying disease onset, slowing progression, and delaying mortality.
Arimoclomol is a hydroxylamine derivative that acts as a coinducer of heat shock protein (HSP) expression, which is increased in chronic disease and offers a powerful cytoprotective mechanism. In ALS mice with the SOD1 G93A mutation, Kieran et al. (2004) found that treatment with arimoclomol resulted in delay in disease progression, improvement in hindlimb muscle function, increase in motoneuron survival, and increase in life span compared to untreated mutant mice. Arimoclomol prolonged the activation of heat shock transcription factor-1 (HSF1; 140580), resulting in an increase in HSP70 (140550) and HSP90 (140571) expression in the treated mutant mice.
Azzouz et al. (2004) reported that a single injection of a VEGF (192240)-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene encoding the mutated G93A form of SOD1 (147450.0008), even when treatment was initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30% without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field to that time.
To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2 subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (see GLUR2, 138247) to SOD1-related motoneuronal death, Tateno et al. (2004) generated choline acetyltransferase (ChAT; 118490)-GluR2 transgenic mice with significantly reduced Ca(2+) permeability of these receptors in spinal motoneurons. Crossbreeding of the Sod1(G93A) transgenic mouse model of ALS with ChAT-GluR2 mice led to marked delay of disease onset, mortality, and the pathologic hallmarks such as release of cytochrome c from mitochondria, induction of Cox2 (600262), and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species accumulated in 2 fractions (P1, composed of nuclei and certain kinds of cytoskeletons such as neurofilaments and glial fibrillary acidic protein (GFAP; 137780), and P2, composed of mitochondria) long before disease onset and then extensively accumulated in the P1 fractions by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca(2+) influx through atypical motoneuronal AMPA receptors thus promoted a misfolding of mutant SOD1 protein and eventual death of these neurons.
Using unbiased transcript profiling in the Sod1G93A mouse model of ALS, Lincecum et al. (2010) identified a role for the costimulatory pathway, a key regulator of immune responses. Furthermore, Lincecum et al. (2010) observed that this pathway is upregulated in the blood of 56% of human patients with ALS. A therapy using a monoclonal antibody to CD40L (300386) was developed that slowed weight loss, delayed paralysis, and extended survival in an ALS mouse model.
Meissner et al. (2010) found that G93A mutant SOD1 activated caspase-1 (CASP1; 147678) and CASP1-mediated secretion of mature IL1-beta (147720) in a dose-dependent manner in microglia and macrophages. In cells in which CASP1 was activated, there was rapid endocytosis of mutant SOD1 into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm dampened the proinflammatory response. Mutant SOD1 induced caspase activation through a gain of amyloid conformation, not through its enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the life span of mutant Sod1 mice and was associated with decreased microgliosis and astrogliosis; however, age at disease onset was not affected. Treatment of mutant mice with an IL1 receptor inhibitor also extended survival and improved motor performance. The findings suggested that IL1-beta contributes to neuroinflammation and disease progression in ALS.
Other Animal Models
To determine whether increased SOD1 protects the heart from ischemia and reperfusion, Wang et al. (1998) performed studies in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could be performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in both myocytes and endothelial cells. In nontransgenic hearts following 30 minutes of global ischemia, a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1, the burst of superoxide generation was almost totally quenched, and this was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrated that superoxide is an important mediator of postischemic injury and that increased intracellular SOD1 dramatically protects the heart from this injury.
To test the hypothesis that chronic and unrepaired oxidative damage occurring specifically in motor neurons is a critical causative factor in aging, Parkes et al. (1998) generated transgenic Drosophila that expressed human SOD1 specifically in adult motor neurons. The authors showed that overexpression of the SOD1 gene in motor neurons extended normal life span of the animals by up to 40% and rescued the life span of a short-lived Sod null mutant. Elevated resistance to oxidative stress suggested that the life span extension observed in these flies was due to enhanced metabolism of reactive oxygen.
Green et al. (2002) excluded the Sod1 gene as a candidate for canine spinal muscular atrophy.
Imamura et al. (2006) generated Sod1 -/- mice and observed age-related changes of the retina similar to the key elements of human age-related macular degeneration (ARMD; see 603075), including drusen, thickened Bruch membrane, and choroidal neovascularization. Imamura et al. (2006) suggested that oxidative stress may play a causative role in ARMD and concluded that SOD1 has a critical role in protecting the retinal pigment epithelium from age-related macular degeneration.
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous G-to-A transition in exon 2 of the SOD1 gene, resulting in a gly37-to-arg (G37R) substitution.
By transient expression in primate cells, Borchelt et al. (1994) found that the G37R mutant protein retained full specific activity, but displayed a 2-fold reduction in polypeptide stability. The G37R mutant displayed similar properties in transformed lymphocytes from an individual heterozygous for the G37R and wildtype SOD1 genes; heterodimeric enzymes composed of mutant and wildtype subunits were detected, but there was no measurable diminution in the stability and activity of the wildtype subunits. The authors concluded that mutants such as G37R with modest losses in activity involving only the mutant subunit can still result in motor neuron death. Alternatively, mutant SOD1 may acquire properties that injure motor neurons by one or more mechanisms unrelated to the metabolism of oxygen radicals.
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous C-to-G transversion in exon 2 of the SOD1 gene, resulting in a leu38-to-val (L38V) substitution.
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous G-to-A transition in exon 2 of the SOD1 gene, resulting in a gly41-to-ser (G41S) substitution.
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous G-to-A transition in exon 2 of the SOD1 gene, resulting in a gly41-to-asp (G41D) substitution.
In a baculovirus expression system in insect cells, Fujii et al. (1995) found that the G41D enzyme exhibited 47% of wildtype SOD1 activity.
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous A-to-G transition in exon 2 of the SOD1 gene, resulting in a his43-to-arg (H43R) substitution.
In a baculovirus expression system in insect cells, Fujii et al. (1995) found that the H43R enzyme exhibited 66% of wildtype SOD1 activity.
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-C transversion in exon 4 of the SOD1 gene, resulting in a gly85-to-arg (G85R) substitution.
By transient expression in COS cells, Borchelt et al. (1994) found that the G85R mutant protein was enzymatically inactive. However, Fujii et al. (1995) found that the G85R enzyme exhibited 99% of wildtype SOD activity in a baculovirus expression system in insect cells.
Bruijn et al. (1997) found that the G85R mutant protein retained SOD1 activity in studies of transgenic mice with the G85R mutation. However, even low levels of the mutant protein caused motor neuron disease characterized by extremely rapid clinical progression. Initial indicators of disease were astrocytic inclusions that stained intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons. Astrocytic inclusions escalated markedly as disease progressed, concomitant with a decrease in the glial glutamate transporter (GLT1; 600300). The authors concluded that G85R mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.
Using the G85R mutation in transgenic mouse experiments, Bruijn et al. (1998) demonstrated that neither elimination nor elevation of wildtype SOD1 had any effect on mutant-mediated disease. The fact that aggregates containing SOD1 were common to disease caused by different mutants implied that coaggregation of an unidentified essential component or aberrant catalysis by misfolded mutants underlies, in part, mutant-mediated toxicity.
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-T transversion in exon 4 of the SOD1 gene, resulting in a gly93-to-cys (G93C) substitution.
Regal et al. (2006) reported the clinical features of 20 ALS patients from 4 families with the G93C mutation. Mean age at onset was 45.9 years, and all patients had slowly progressive weakness and atrophy starting in the distal lower limbs. Although symptoms gradually spread proximally and to the upper extremities, bulbar function was preserved. None of the patients developed upper motor neuron signs. Postmortem findings of 1 patient showed severe loss of anterior horn cells and loss of myelinated fibers in the posterior column and spinocerebellar tracts, but only mild changes in the lateral corticospinal tracts. Lipofuscin and hyaline inclusions were observed in many neurons. Patients with the G93C mutation had significantly longer survival compared to patients with other SOD1 mutations.
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-C transversion in exon 4 of the SOD1 gene, resulting in a gly93-to-ala (G93A) substitution.
Yim et al. (1996) observed that overexpression of mutant human H93A SOD1 in Sf9 insect cells resulted in enhanced generation of free radicals compared to wildtype SOD1, as measured by the spin trapping method. The effect was more intense at lower peroxide concentrations due to a small, but reproducible, decrease in the value of K(m) for peroxide for the G93A mutant, while the k(cat) was identical for the mutant and wildtype. The G93A mutant and wildtype enzymes had identical dismutation activity. Yim et al. (1996) concluded that ALS symptoms observed in G93A transgenic mice were not caused by the reduction of SOD1 activity, but rather were induced by a gain-of-function enhancement of the free radical-generating function. The findings were consistent with x-ray crystallographic studies showing that the active channel of the G93A mutant is slightly larger than that of the wildtype enzyme, rendering it more accessible to peroxide. See also Kostic et al. (1997).
Wiedau-Pazos et al. (1996) showed that the G93A mutant SOD1 enzyme catalyzed the oxidation of a model substrate (spin trap 5,5-prime-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher rate than that seen with the wildtype enzyme. Catalysis of this reaction by the mutant enzyme was more sensitive to inhibition by the copper chelators diethyldithiocarbamate and penicillamine than was catalysis by wildtype SOD1. The same 2 chelators reversed the apoptosis-inducing effect of the mutant enzyme expressed in a neural cell line. The findings were interpreted to mean that oxidative reactions catalyzed by mutant SOD1 enzymes initiate the neuropathologic changes in familial ALS.
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified an A-to-G transition in exon 4 of the SOD1 gene, resulting in a glu100-to-gly (E100G) substitution.
Winterbourn et al. (1995) demonstrated decreased thermal stability of the mutant E100G enzyme. Extracts containing the mutant had an average 68% of normal SOD activity. On heating at 65 degrees centigrade, these extracts lost activity at twice the rate of extracts containing only normal enzyme.
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a C-to-G transversion in exon 4 of the SOD1 gene, resulting in a leu106-to-val (L106V) substitution.
Kawamata et al. (1994) identified this mutation in a Japanese ALS family.
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a T-to-C transition in exon 4 of the SOD1 gene, resulting in an ile113-to-thr (I113T) substitution.
Jones et al. (1993) identified the I113T substitution in 3 of 56 patients with sporadic ALS drawn from a population-based study in Scotland. Jones et al. (1995) found the I113T mutation in 3 sporadic ALS cases and 3 unrelated familial cases of ALS in Scotland. Because of early death of parents of probands, together with illegitimacy in families, some of the apparently sporadic cases may have been familial. The average age at onset in patients with the I113T mutation was cited as 61.2 years, with mean survival of 1.6 years.
Hayward et al. (1996) reported 6 additional cases in Scotland with the I113T mutation and a common haplotype despite no evidence of relatedness. Brock (1998) reported that he and his coworkers had found another 3 cases in the north of England with the I113T mutation and the identical genetic background, one that is rare in the general population.
Kikugawa et al. (1997) performed mutation analyses of the SOD1 gene in 23 ALS patients (3 familial and 20 sporadic) from the Kii Peninsula of Japan and its vicinity, where a relatively high incidence of familial ALS had been observed. In 2 of the 23 patients, they identified heterozygosity for the I113T mutation. The mutation had been reported to be associated with the formation of neurofibrillary tangles, which was a characteristic feature of ALS in the Kii Peninsula.
Deng et al. (1993) found that the ala4-to-val (A4V) mutation in exon 1 of the SOD1 gene is the most frequent basis for familial amyotrophic lateral sclerosis (105400). This mutation was found in affected members of 8 unrelated families. One of the families with the A4V mutation was the Farr family reported by Brown (1951, 1960).
Rosen et al. (1994) confirmed that the A4V mutation is the most commonly detected of all SOD1 mutations in familial ALS, and that it is among the most clinically severe. In comparison with other ALS families, the exon 1 mutation is associated with reduced survival time after onset: 1.2 years as compared to 2.5 years for all other familial ALS patients.
Wiedau-Pazos et al. (1996) showed that the A4V mutant SOD1 enzyme catalyzed the oxidation of a model substrate (spin trap 5,5-prime-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher rate than that seen with the wildtype enzyme. Catalysis of this reaction by the mutant enzyme was more sensitive to inhibition by the copper chelators diethyldithiocarbamate and penicillamine than was catalysis by wildtype SOD1. The same 2 chelators reversed the apoptosis-inducing effect of the mutant enzyme expressed in a neural cell line. The findings were interpreted to mean that oxidative reactions catalyzed by mutant SOD1 enzymes initiate the neuropathologic changes in familial ALS.
Rakhit et al. (2007) used a specific SOD1 antibody to identify misfolded SOD1 within degenerating motor neurons in the spinal cord from an individual with ALS due to the A4V mutation. The findings provided evidence that misfolded SOD1 plays a toxic or pathogenic role in ALS.
Saeed et al. (2009) identified a single 5.86-cM haplotype encompassing the A4V variant in 54 white North American ALS patients that was not found in 96 controls (p = 3 x 10(-11)), indicating a founder effect. To determine the origin, several additional cohorts were genotyped, including 54 North American, 3 Swedish, and 6 Italian patients with the A4V mutation, 66 ALS patients with non-A4V SOD1 mutations, 96 patients with sporadic ALS, and 96 white, 17 African American, 53 Chinese, 11 Amerindian, and 12 Hispanic healthy controls. The strength of association of the white founder haplotype progressively decreased when other ethnicities were used as controls, and almost disappeared when compared to Amerindians, indicating that the A4V mutation was introduced from Amerindians who migrated from Asia into North America. The associated European haplotype was different from the North American haplotype, indicating an Amerindian founder effect (accounting for 82%) and a European founder effect (accounting for 18%) for A4V in North America. Amerindians were both homozygous and heterozygous, whereas Europeans were only homozygous, for nearby SNPs. The age of the A4V mutation was estimated to be 458 +/- 59 years (range, 398 to 569 years). Saeed et al. (2009) postulated that A4V was introduced into the white population by Amerindians about 400 to 500 years ago at the time of the Jamestown and Plymouth landings. Furthermore, there were no Amerindians with ALS in their database, suggesting either that the mutation became extinct in Amerindians or that they have an additional protective effect.
In 2 Japanese families with unusually slow progression of ALS (105400), Aoki et al. (1993) found an A-to-G transition in exon 2 of the SOD1 gene that resulted in a his46-to-arg (H46R) substitution. His46 is a highly conserved residue within the active site of the enzyme, and the mutation was predicted to affect copper binding. The mutation was not found in 27 Japanese patients with sporadic ALS or 57 unrelated normal control subjects. Functional expression studies showed that the mutant enzyme activity was reduced by about 20%. Aoki et al. (1993) suggested that the H46R substitution influences only the active site and does not interfere with dimer formation, which had been reported for other SOD1 mutations. Affected individuals showed a relatively mild form of the disorder, with symptoms appearing in the arms more than 5 years after onset and bulbar signs appearing more than 8 years after initial symptoms in the legs. The mean survival after onset was 17.3 years in the Japanese cases as compared with 1.5 years and 2.4 years in Caucasian families and 2.5 years in Japanese families with different mutations. Aoki et al. (1994) presented in greater detail the data reported by Aoki et al. (1993).
Liu et al. (2000) determined that mutant H46R SOD1 binds neither Cu(2+) nor Co(2+) at the native copper-binding site, but forms a new copper-binding site at cys111 on the surface near the site of dimer formation. Insertion of copper ions into SOD1 under normal conditions in vivo requires the presence of a copper chaperone, CCS (603864). Liu et al. (2000) hypothesized that cys111 is an intermediate docking site for Cu(2+) during SOD1 biosynthesis and that it transfers Cu(2+) to the final destination in the active site of the wildtype enzyme.
Kawamata et al. (1994) made reference to a Japanese family with ALS (105400) associated with a G-to-A transition in the SOD1 gene, resulting in an ala4-to-thr (A4T) substitution. Nakano et al. (1994) reported this family in full. See A4V (147450.0012) for a mutation involving the same codon.
In 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS (105400), Andersen et al. (1995) identified a homozygous mutation in exon 4 of the SOD1 gene, resulting in an asp90-to-ala (D90A) substitution. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Consanguinity was present in several of the families. The age at onset of symptoms ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1-4 years disease duration in all patients; none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype similar to that of the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Four patients with apparently sporadic ALS were also found to carry the mutations. Andersen et al. (1995) concluded that familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms.
Robberecht et al. (1996) identified a heterozygous D90A mutation in affected members of 2 families with ALS and in a patient with apparently sporadic ALS. Aguirre et al. (1999) found the D90A mutation in heterozygous state in affected members of 2 families and in 1 apparently sporadic case of ALS. Direct sequencing of exons 1 through 5 showed no additional mutations in the SOD1 gene in these patients and the D90A mutation was not found on 150 normal chromosomes.
In a worldwide haplotype study of 28 pedigrees with the D90A mutation, Al-Chalabi et al. (1998) found that 20 recessive families shared the same founder haplotype, regardless of geographic location, whereas several founders existed for the 8 dominant families. The findings confirmed that D90A can act in a dominant fashion in keeping with all other SOD1 mutations. Al-Chalabi et al. (1998) proposed that a tightly linked protective factor modifies the toxic effect of mutant SOD1 in recessive families.
Gellera et al. (2001) found homozygosity for the D90A mutation in a sporadic case of ALS.
In 2 sibs with ALS from a family described by Khoris et al. (2000), Hand et al. (2001) identified compound heterozygosity for D90A and D96N (147450.0032). A third sib with the disease died before testing. Further examination of the family identified the D90A mutation alone in 2 unaffected members and the D96N mutation alone in 4 unaffected members. There were no individuals homozygous for either mutation, and no unaffected individual with both mutations was identified. Hand et al. (2001) concluded that both mutations, which occur in the same region of the protein, are required for disease. The authors emphasized that this is the first report of compound heterozygosity for the SOD1 gene in an ALS patient and suggested that the findings may have implications for the interpretation of inheritance patterns in ALS families.
Using PET scanning, Turner et al. (2007) found that ALS patients homozygous for the D90A substitution had a 12% decrease in 5-HT1A receptor (5HTRA1; 109760) binding potential compared to healthy controls. The decreased binding among patients was most significant in the temporal lobes. Patients with sporadic ALS without the D90A substitution had a 21% decrease in binding potential. Turner et al. (2007) suggested that patients with the D90A mutation may have decreased cortical vulnerability compared to other ALS patients, which may correlate with the slower progression observed in D90A carriers.
In a Japanese family transmitting amyotrophic lateral sclerosis (105400) with marked phenotypic variability, Ikeda et al. (1995) identified an A-to-T mutation in exon 4 of the SOD1 gene, resulting in an ile104-to-phe (I104F) substitution within a highly conserved loop VI Greek key domain. This same domain has been affected by other disease-associated SOD1 mutations (L106V; 147450.0010 and I113T; 147450.0011). The activity of the mutant I104F enzyme was decreased by 43%. Age of onset varied from 6 to 55 years with initial symptoms either in the lower or upper extremities. The duration of the disease varied from 3 to 38 years. Two asymptomatic carriers who died from other causes at ages 59 and 34, respectively, had affected offspring.
Sapp et al. (1995) reported a leu144-to-ser (L144S) mutation in the SOD1 gene in a family with apparently slow progression of amyotrophic lateral sclerosis (105400). This substitution is in close proximity to the active center of the SOD1 enzyme at arginine 143.
Sapp et al. (1995) reported an ala145-to-thr (A145T) mutation in the SOD1 gene in a family with amyotrophic lateral sclerosis (105400).
In affected members of a family with ALS (105400), Sapp et al. (1995) identified a T-to-G transversion in intron 4 of the SOD1 gene, resulting in an alternatively spliced mRNA and a SOD1 protein with 3 amino acids (phe-leu-gln) inserted between exons 4 and 5 following residue 118.
Morita et al. (1996) identified a 2-bp mutation in exon 1 of the SOD1 gene in a 59-year-old woman who developed rapidly progressive ALS (105400). The mutation predicted a cys6-to-phe (C6F) substitution. Erythrocyte SOD1 activity was 25.3% of control values. Since the only other affected family member was the deceased father, segregation of the mutation with the disorder was not confirmed.
In a woman with ALS (105400), Kostrzewa et al. (1996) identified a T-to-C transition in exon 5 of the SOD1 gene, resulting in an ile151-to-thr (I151T) substitution. The patient had onset at age 48 years of progressive dysarthria and dysphagia, followed 9 months later by distal weakness of the legs and then weakness of her left hand. The mutation appeared to affect formation of dimers of the protein and was the most C-terminal amino acid change in SOD1 described to that time. (Kostrzewa et al. (1996) mistakenly stated that the T-to-C transition resulted in the 'substitution of an isoleucine (ATC) for a threonine (ACC)' but also stated that 'the isoleucine at position 151...is evolutionarily highly conserved in most vertebrates.')
In a Scottish patient with sporadic ALS (105400), Jones et al. (1994) identified a G-to-A transition in the SOD1 gene, resulting in a glu21-to-lys (E21K) substitution. The transition occurs at a CpG dinucleotide and may have arisen via deamination of methylcytosine.
In a 65-year-old Japanese man with ALS (105400), Watanabe et al. (1997) identified a mutation in the SOD1 gene, resulting in a ser134-to-asn (S134N) substitution. The patient had first noted right lower limb muscle weakness at age 63. The proband's younger brother was also affected with onset of muscle weakness at age 52, followed by rapidly progressive muscle weakness and atrophy of all limbs, and bulbar signs. He died of respiratory disease 9 months after onset. Although neither patient showed upper motor neuron signs throughout the course of the disease, the finding of an SOD1 mutation was consistent with a form of familial ALS. Both parents died of disorders other than neurologic diseases at ages 84 and 49, respectively. Other relatives of the patient had no similar neurologic disease.
In a Japanese family with 4 members affected by ALS (105400) in 3 generations, Aoki et al. (1995) identified a mutation in the SOD1 gene that resulted in a leu84-to-val (L84V) substitution. The enzymatic activity of Cu/Zn SOD of skin fibroblasts was reduced to 75% of control values. The progression of the disease was very rapid, but the age of onset varied with sex and with generation within the family. The proband first noted weakness and atrophy in the left hand at age 38 years. Within 3 months, weakness developed in all 4 extremities and he died of pneumonia 1.5 years after the onset of the disease.
In a patient with ALS (105400), Kawamata et al. (1997) identified a G-to-A transition in the SOD1 gene, resulting in a gly16-to-ser (G16S) substitution. The patient noted difficulty in writing at age 18 years. Thereafter, muscle weakness progressed rapidly and the patient could not walk unassisted. Mechanical ventilation was required at age 19.
In a 58-year-old male with a family history of ALS (105400) and with a personal history of progressive muscle weakness and atrophy for 4 years, Zu et al. (1997) found a T-to-A transversion in the SOD1 gene, resulting in a leu126-to-ter (L126X) substitution. The mutation resulted in the truncation of most of the polypeptide segment encoded by exon 5 and resulted in a familial ALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the toxic functions of mutant SOD1 associated with ALS. The mutant enzyme was present at very low levels in the patient, suggesting elevated toxicity compared to mutant enzymes with single site substitutions. This increased toxicity probably arose from the extreme structural and functional changes in the active site channel, beta-barrel fold, and dimer interface observed in the mutant enzyme, including the loss of native dismutase activity. In particular, the truncation of the polypeptide chain dramatically opens the active site channel, resulting in a marked increase in the accessibility and flexibility of the metal ions and side chain ligands of the active site of the enzyme. Zu et al. (1997) proposed that these structural changes cause a decrease in substrate specificity and an increase in the catalysis of harmful chemical reactions such as peroxidation.
In a 72-year-old male with a family history of ALS (105400) and slowly progressive symptoms of muscle weakness and atrophy, Zu et al. (1997) identified an intronic mutation (A-to-G) in SOD1 at the nucleotide 11 bases upstream from the intron-junction of exon 5. This splice junction mutation resulted in alternative splicing in the mRNA with truncation of most of the polypeptide segment encoded by exon 5. The consequences were thought to be similar to those of the leu126-to-ter mutation (147450.0026).
Orrell et al. (1997) found a heterozygous gly72-to-ser (G72S) substitution in exon 3 of the SOD1 gene in a brother and sister with ALS (105400). The brother had onset at age 47 with weakness of the right foot; the sister had died with a diagnosis of ALS at the age of 49 years. This was the first exon 3 mutation to be described; over 50 different mutations involving exons 1, 2, 4, and 5 had previously been described.
In a 67-year-old patient with familial ALS (105400), Penco et al. (1999) identified a mutation in exon 1 of the SOD1 gene, resulting in a gly12-to-arg (G12R) substitution in a region outside the active site of the enzyme. The substitution may lead to local distortion strain in the protein structure. The enzymatic activity of the mutated SOD1 was 80% of normal. The patient had onset of symptoms at age 63 years, and the disorder showed unusually slow progression. The patient's father had died at age 59 with a diagnosis of ALS recognized during the last year of his life. His clinical features were very similar to those observed in the proband. His first symptoms were walking difficulties associated with weak leg muscles. Tendon reflexes were markedly hyperactive, but Achilles reflexes were absent. Hand and bulbar involvement started late in the course of the illness.
Penco et al. (1999) had originally identified this mutation as GLY12ALA. Gellera et al. (2001) pointed out that the mutation was in fact a change from GGC (gly) to CGC (arg). They likewise described a patient with slowly progressive ALS due to a G12R substitution in exon 1 of the SOD1 gene.
In a familial case of slowly progressing ALS (105400), Gellera et al. (2001) found a de novo T-to-G transversion in exon 2 of the SOD1 gene, resulting in a phe45-to-cys (F45C) substitution. Onset occurred at 59 years of age in the distal muscles of the upper limbs.
In a 24-year-old man with sporadic ALS (105400), Alexander et al. (2002) identified a heterozygous 112A-G transition in exon 4 of the SOD1 gene, resulting in a his80-to-arg (H80R) substitution. The patient presented with a 4-month history of left leg weakness, and developed rapidly progressive weakness in all 4 limbs and bulbar musculature, manifesting as quadriplegia, dysarthria, and dysphagia over the subsequent 8 months. He died from pneumonia 18 months after the onset of symptoms. Neuropathologic examination showed anterior horn cell degeneration, prominent gliosis, and Bunina bodies in both the spinal cord and brain stem. There was no involvement of the corticospinal tract. Ubiquitinated inclusions were demonstrated within anterior horn cells, and SOD1-immunoreactive inclusions were identified. There was no family history of any form of neuromuscular disorder. His parents, maternal grandfather, and 2 sibs did not carry the mutation, and it was not identified in 150 unaffected Irish controls. (Alexander et al. (2002) reported the mutation as histidine to arginine at codon 80, but incorrectly symbolized the mutation as H80A.)
In 2 sibs with ALS (105400) from a family described by Khoris et al. (2000), Hand et al. (2001) identified compound heterozygosity for 2 mutations in the SOD1 gene: a G-to-A transition resulting in an asp96-to-asn substitution (D96N), and D90A (147450.0015). A third sib with the disease died before testing. Further examination of the family identified the D90A mutation alone in 2 unaffected members and the D96N mutation alone in 4 unaffected members. There were no individuals homozygous for either mutation, and no unaffected individual with both mutations was identified. Hand et al. (2001) concluded that both mutations, which occur in the same region of the protein, are required for disease. The authors emphasized that this was the first report of compound heterozygosity for the SOD1 gene in an ALS patient and suggested that the findings may have implications for the interpretation of inheritance patterns in ALS families.
In affected members of a family segregating amyotrophic lateral sclerosis (105400), Elshafey et al. (1994) identified a gly93-to-arg (G93R) mutation in exon 4 of the SOD1 gene.
In a Canadian patient of Filipino origin with ALS (105400), Zinman et al. (2009) identified a homozygous 6-bp deletion (GGACCA) in exon 2 of the SOD1 gene, resulting in the removal of 2 amino acids (gly27 and pro28) in a conserved part of loop II. The patient had onset of leg and arm weakness at age 51, and later developed bulbar symptoms with death from respiratory failure at age 55. The diagnosis was confirmed by autopsy. The patient's father and paternal uncle were also affected and died at ages 66 and 58, respectively. Genotyping of available family members identified 8 unaffected heterozygous carriers and a common haplotype, consistent with a founder effect. Reconstruction of the genotype in the patient's affected father showed that he was heterozygous for the mutation. SOD1 undergoes naturally occurring alternative splicing of exon 2, and the mutation was predicted to enhance this splicing. RT-PCR studies showed alternative splicing with 2 transcripts: 1 without exon 2 and another without exons 2 and 3, both of which result in premature termination. The abundance of the transcript lacking exons 2 and 3 was similar in all individuals, including an individual without the mutation. However, expression of the transcript without exon 2 was enhanced in mutation carriers, with the highest abundance in the homozygous proband. Spinal cord samples from the proband showed significantly decreased SOD1 protein expression (40% less than wildtype), and erythrocytes showed 50% decreased SOD1 enzyme activity. The mutation was not found in 179 Filipino controls. Zinman et al. (2009) concluded that the 6-bp deletion represents a reduced penetrance allele in the heterozygous state, resulting from modification of naturally occurring alternative splicing.
In affected members of a French family with ALS1 (105400), Valdmanis et al. (2009) identified a heterozygous C-to-G transversion in intron 4 of the SOD1 gene (358-304C-G), resulting in the inclusion of a 43-bp cryptic exon 304 bp before exon 5 in the SOD1 mRNA. This resulted in the introduction of 7 amino acids before a stop codon, causing premature termination of the protein product. Valdmanis et al. (2009) noted the unusual genetic mechanism involved and emphasized the difficulty in detecting such a mutation.
In a 3-year-old girl, born of consanguineous Afghan parents, with progressive spastic tetraplegia and axial hypotonia (STAHP; 618598), Andersen et al. (2019) identified a homozygous 1-bp duplication (c.335dupG, NM_000454.4) in exon 4 of the SOD1 gene, resulting in a frameshift and premature termination (Cys112TrpfsTer11). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was found in the heterozygous state in each unaffected parent. Patient cells showed absent SOD1 activity, and cells from the clinically unaffected heterozygous parents had about 50% residual activity. Presence of a mutant 13-kD protein was detected in cells from both the patient and parents. Patient fibroblasts showed impaired growth in 19% oxygen, indicating extreme oxygen sensitivity.
Independently and simultaneously, Park et al. (2019) identified the same homozygous mutation in an Afghan boy, also born of consanguineous parents, with a similar phenotype. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. SOD1 activity was undetectable in patient cells, and clinically unaffected family members who were heterozygous for the mutation had about 50% residual SOD1 activity compared to controls.
In a 25-month-old Arab Muslim girl, born to consanguineous parents, with progressive spastic tetraplegia and axial hypotonia (STAHP; 618598), Ezer et al. (2022) identified a homozygous 3-bp deletion (c.357_357+2delGGT, NM_000454.5) in the SOD1 gene resulting in a deletion of val119 or val120. The mutation was identified by trio whole-exome sequencing, and the parents were shown to be mutation carriers. Sequencing of cDNA from patient lymphocytes confirmed the deletion of val119 or val120. SOD enzyme activity and protein expression were absent in patient erythrocytes and were reduced to about 50% of control levels in her parents.
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