SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk

Abstract

Objective Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer’s disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that under expression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. Methods We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation. Results Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ. Interpretations These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…We found no other binding sites for APP outside the CR-cluster in SorLA either within the cytoplasmic tail, previously suggested as a possible linker between the two proteins (36), or within other regions of the composite SorLA extracellular domain. This result was surprising, as the VPS10p domains from the homologous receptors sortilin and SorCS1 have recently been suggested as novel APP interaction domains (29,31,53). For SorCS1, it is possible that the leucine-rich domain also contributes to the binding of APP.…”

“…We previously identified an interaction between the isolated SorLA CR-cluster and APP (21). However, as the VPS10p domain of the SorLA-related proteins sortilin (29) and SorCS1 (30,31) have also been reported to interact with APP, we wanted to determine whether the CR-cluster is the only site for APP binding within SorLA. Therefore, we generated a SorLA variant without the CR-domains to further study APP binding.…”

SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells

“…Its functions evolved from transport of specific proteins to lysosomes to SG biogenesis. This pathway is fundamental to a diversity of biological processes and thus explains why Sorcs1, in addition to diabetes, is associated with other diseases, including diabetes complications and Alzheimer's disease (61)(62)(63)(64).…”

Recalculation of 23 mouse HDL QTL datasets improves accuracy and allows for better candidate gene analysis

“…This gene codes for a Vsp10p-D receptor family member transmembrane protein, which functions to sort and traffi c proteins ( 32 ). Genetic variation in this gene has been associated with both the development of type II diabetes ( 33,34 ) and risk for development of Alzheimer disease ( 35 ). These two diseases are correlated with serum lipid levels and genetic variation in another Vsp10p-D receptor gene, Sort1 , which has been linked to serum LDL levels ( 36,37 ).…”