Alternative titles; symbols
HGNC Approved Gene Symbol: SORL1
Cytogenetic location: 11q24.1 Genomic coordinates (GRCh38): 11:121,452,314-121,633,763 (from NCBI)
SORL1 is a mosaic protein with a domain structure that suggests it is a member of both the vacuolar protein sorting-10 (Vps10) domain-containing receptor family and the low density lipoprotein receptor (LDLR; 606945) family (Jacobsen et al., 2001).
Jacobsen et al. (1996) sought to identify novel receptors capable of binding the receptor-associated protein RAP (104225). Using a RAP affinity column, they identified the SORL1 protein, which they termed SORLA1. They isolated the corresponding cDNA from human brain and T-lymphocyte libraries. The cDNA encodes a 2,186-amino acid polypeptide with homology to yeast Vps10 and the RAP-binding receptor gp95/sortilin (602458). Jacobsen et al. (1996) identified the following features of the SORL1 protein sequence: a secretory signal sequence, a large luminal domain, a furin cleavage site, a cluster of 11 low-density lipoprotein receptor class A repeats, 6 fibronectin type III repeats, a single transmembrane domain, and a 56-amino acid cytoplasmic tail containing a putative internalization motif. Using Northern blot analysis, Jacobsen et al. (1996) found that SORL1 is expressed as a 10.5-kb transcript in brain, spinal cord, and testis, with weaker expression detected in some, but not all, tissues tested.
Jacobsen et al. (2001) produced a soluble SORL1 minireceptor containing residues 1 to 731, encompassing the 53-amino acid propeptide, the Vps10 domain, and the first 7 residues of the adjacent beta-propeller domain. They analyzed SORL1 minireceptors secreted from transfected Chinese hamster ovary (CHO) cells and found that SORL1 was activated by furin (136950)-mediated cleavage and removal of the propeptide. The released propeptide bound SORL1 in a pH-dependent manner and inhibited binding of other ligands to overlapping sites in the Vps10 domain, including the mammalian homolog of hydra head activator (HA) peptide, neurotensin (162650), and RAP. Full-length SORL1 also bound ApoE (107741) and lipoprotein lipase (238600) via a different domain, likely the central LDLR class A repeat cluster. In cells transfected with full-length SORL1, most receptors were found in the Golgi apparatus, but about 10% were expressed on the cell surface, where they mediated endocytosis and degradation of bound ligand.
After transfection of full-length human SORL1 in CHO cells, Lintzel et al. (2002) detected SORL1 associated with the membrane and SORL1 secreted into the conditioned medium. The membrane-bound protein contained the intracellular domain but lacked the propeptide, whereas the secreted protein lacked both the intracellular domain and the propeptide. SORL1-transfected COS-7 cells, which have very low levels of furin-like proteases, expressed predominantly unprocessed SORL1. Cotransfection with a furin-encoding vector led to increased release of SORL1 from COS-7 cells into the medium, confirming that furin cleaves the SORL1 propeptide. Lintzel et al. (2002) assayed the binding properties of several SORL1 truncation mutants expressed in human neuroendocrine and neuroblastoma cell lines and found that RAP interacted primarily with the LDLR class A repeats, but also with the Vps10 domain. The HA peptide and SORL1 propeptide interacted specifically with the Vps10 domain. In both cell lines, the SORL1 propeptide antagonized mitosis and cell proliferation induced by HA peptide.
Zhu et al. (2004) stated that SORL1 expression causes elevated levels of Upar (PLAUR; 173391) in rabbit aorta smooth muscle cells (SMCs). They found that both membrane-spanning and secreted soluble forms of mammalian Sorl1 had the capacity to bind Upar, and Sorl1 colocalized with Upar on the cell surface. Sorl1 overexpression enhanced Upar binding on the cell surface, but it inhibited LDLR-related protein (LRP1; 107770)-mediated Upar binding and internalization. Sorl1 was highly expressed in the plaque area of ApoE-knockout mice, particularly in intimal SMCs at the border between intima and media. Zhu et al. (2004) concluded that SORL1 may be involved in the process of atherosclerosis and arterial remodeling.
Using a differential DNA microarray screen, Scherzer et al. (2004) found that SORL1 was consistently downregulated approximately 2-fold in lymphoblasts from patients with Alzheimer disease (AD; 104300). Immunohistochemical analysis of 13 AD brains showed a dramatic loss of SORL1 staining in frontal cortex pyramidal neurons compared to controls. Staining in glial cells was not decreased. Western blot analysis confirmed a 25% reduction of the SORL1 protein in AD frontal cortex. Scherzer et al. (2004) noted that the structure and function of SORL1 as a mosaic ApoE receptor strongly suggested that it plays a role in AD. Sager et al. (2007) also found a correlation between decreased SORL1 expression and impaired cognitive function among 34 individuals, including 10 patients with AD, 15 with mild cognitive impairment, and 9 controls. The mean SORL1 levels among patients with mild cognitive impairment was between that of controls and AD patients, but further analysis detected 2 groups within the mildly affected individuals. The results suggested that decreased SORL1 expression reflects cognitive performance and may predispose individuals with mild cognitive impairment to the development of Alzheimer disease.
Jacobsen et al. (1996) used in situ hybridization to map the SORL1 gene to human chromosome 11q23.2-q24.2.
Association with Alzheimer Disease
The recycling of the amyloid precursor protein (APP; 104760) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (A-beta) in Alzheimer disease (AD; 104300). Rogaeva et al. (2007) reported that inherited variants of the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease (LOAD). These variants, which occur in at least 2 different clusters of intronic sequences within the SORL1 gene, may regulate tissue-specific expression of SORL1. Rogaeva et al. (2007) also showed that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into A-beta-generating compartments. The data suggested that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease. Rogaeva et al. (2007) tested SNPs of SORL1 in 6 data sets composed of families with late-onset familial Alzheimer disease. In sharp contrast to the APOE gene (107741), where the APOE4 allele is associated with Alzheimer disease in most data sets, no single SORL1 SNP or haplotype was associated with increased risk for Alzheimer disease in all 6 data sets. Rogaeva et al. (2007) presented reasons for thinking that the association between SORL1 and Alzheimer disease is not spurious.
Liu et al. (2007) was unable to confirm linkage of Alzheimer disease to SORL1 on 11q23.2-q24.2; instead, their analysis pointed to the OPCML gene (600632) at 11q25 and the HNT gene (607938), also at 11q25.
Lee et al. (2007) reported associations between various SNPs and haplotypes in the SORL1 gene and Alzheimer disease among a total of 296 AD patients comprising 3 cohorts of African American, Caribbean Hispanic, and non-Hispanic white individuals. The findings suggested extensive allelic heterogeneity in SORL1, with specific SNPs associated with specific groups.
Cellini et al. (2009) genotyped 13 SNPs in the SORL1 gene in 251 unrelated patients with sporadic LOAD, 99 patients with sporadic early-onset Alzheimer disease, and 358 healthy controls. Three SNPs, rs661057, rs12364988, and rs641120, in the 5-prime region of the SORL1 gene were significantly associated with LOAD compared with controls (p = 0.002 to 0.03; odds ratio, 1.27 to 1.47). There was a more significant association in women, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. The association was confined to APOE-E4 noncarriers. Several haplotypes composed of SNPs at the 5-prime end of SORL1 were also found to be associated with LOAD. Cellini et al. (2009) concluded that their findings confirm the association between SORL1 and LOAD.
By metaanalysis of previous studies including 12,464 AD cases and 17,929 controls of white or Asian descent, Reitz et al. (2011) showed that multiple SORL1 alleles in distinct linkage disequilibrium blocks are associated with risk for AD in white and Asian populations, demonstrating intralocus heterogeneity in the associations with this gene. Reitz et al. (2011) concluded that their findings provided confirmatory evidence of the association of multiple SORL1 variants with AD risk.
Cellini, E., Tedde, A., Bagnoli, S., Pradella, S., Piacentini, S., Sorbi, S., Nacmias, B. Implication of sex and SORL1 variants in Italian patients with Alzheimer disease. Arch. Neurol. 66: 1260-1266, 2009. [PubMed: 19822782] [Full Text: https://doi.org/10.1001/archneurol.2009.101]
Jacobsen, L., Madsen, P., Jacobsen, C., Nielsen, M. S., Gliemann, J., Petersen, C. M. Activation and functional characterization of the mosaic receptor SorLA/LR11. J. Biol. Chem. 276: 22788-22796, 2001. [PubMed: 11294867] [Full Text: https://doi.org/10.1074/jbc.M100857200]
Jacobsen, L., Madsen, P., Moestrup, S. K., Lund, A. H., Tommerup, N., Nykjaer, A., Sottrup-Jensen, L., Gliemann, J., Petersen, C. M. Molecular characterization of a novel human hybrid-type receptor that binds the alpha(2)-macroglobulin receptor-associated protein. J. Biol. Chem. 271: 31379-31383, 1996. [PubMed: 8940146] [Full Text: https://doi.org/10.1074/jbc.271.49.31379]
Lee, J. H., Cheng, R., Schupf, N., Manly, J., Lantigua, R., Stern, Y., Rogaeva, E., Wakutani, Y., Farrer, L., St. George-Hyslop, P., Mayeux, R. The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch. Neurol. 64: 501-506, 2007. [PubMed: 17420311] [Full Text: https://doi.org/10.1001/archneur.64.4.501]
Lintzel, J., Franke, I., Riedel, I. B., Schaller, H. C., Hampe, W. Characterization of the VPS10 domain of SorLA/LR11 as binding site for the neuropeptide HA. Biol. Chem. 383: 1727-1733, 2002. [PubMed: 12530537] [Full Text: https://doi.org/10.1515/BC.2002.193]
Liu, F., Arias-Vasquez, A., Sleegers, K., Aulchenko, Y. S., Kayser, M., Sanchez-Juan, P., Feng, B.-J., Bertoli-Avella, A. M., van Swieten, J., Axenovich, T. I., Heutink, P., van Broeckhoven, C., Oostra, B. A., van Duijn, C. M. A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am. J. Hum. Genet. 81: 17-31, 2007. [PubMed: 17564960] [Full Text: https://doi.org/10.1086/518720]
Reitz, C., Cheng, R., Rogaeva, E., Lee, J. H., Tokuhiro, S., Zou, F., Bettens, K., Sleegers, K., Tan, E. K., Kimura, R., Shibata, N., Arai, H., and 20 others. Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch. Neurol. 68: 99-106, 2011. Note: Erratum: Arch. Neurol. 68: 293 only, 2011. [PubMed: 21220680] [Full Text: https://doi.org/10.1001/archneurol.2010.346]
Rogaeva, E., Meng, Y., Lee, J. H., Gu, Y., Kawarai, T., Zou, F., Katayama, T., Baldwin, C. T., Cheng, R., Hasegawa, H., Chen, F., Shibata, N., and 29 others. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genet. 39: 168-177, 2007. [PubMed: 17220890] [Full Text: https://doi.org/10.1038/ng1943]
Sager, K. L., Wuu, J., Leurgans, S. E., Rees, H. D., Gearing, M., Mufson, E. J., Levey, A. I., Lah, J. J. Neuronal LR11/SorLA expression is reduced in mild cognitive impairment. Ann. Neurol. 62: 640-647, 2007. [PubMed: 17721864] [Full Text: https://doi.org/10.1002/ana.21190]
Scherzer, C. R., Offe, K., Gearing, M., Rees, H. D., Fang, G., Heilman, C. J., Schaller, C., Bujo, H., Levey, A. I., Lah, J. J. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch. Neurol. 61: 1200-1205, 2004. Note: Erratum: Arch. Neurol. 64: 557 only, 2007. [PubMed: 15313836] [Full Text: https://doi.org/10.1001/archneur.61.8.1200]
Zhu, Y., Bujo, H., Yamazaki, H., Ohwaki, K., Jiang, M., Hirayama, S., Kanaki, T., Shibasaki, M., Takahashi, K., Schneider, W. J., Saito, Y. LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration. Circ. Res. 94: 752-758, 2004. [PubMed: 14764453] [Full Text: https://doi.org/10.1161/01.RES.0000120862.79154.0F]