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 underexpression 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.
| Original language | English |
|---|---|
| Pages (from-to) | 47-64 |
| Number of pages | 18 |
| Journal | Annals of Neurology |
| Volume | 69 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2011 |
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ASJC Scopus subject areas
- Neurology
- Clinical Neurology
Cite this
SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk. / Reitz, Christiane; Tokuhiro, Shinya; Clark, Lorraine N.; Conrad, Christopher; Vonsattel, Jean Paul; Hazrati, Lili Naz; Palotás, András; Lantigua, Raphael; Medrano, Martin; Jiménez-Velázquez, Ivonne Z.; Vardarajan, Badri; Simkin, Irene; Haines, Jonathan L.; Pericak-Vance, Margaret A; Farrer, Lindsay A.; Lee, Joseph H.; Rogaeva, Ekaterina; St. George-Hyslop, Peter; Mayeux, Richard.
In: Annals of Neurology, Vol. 69, No. 1, 01.01.2011, p. 47-64.Research output: Contribution to journal › Article
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TY - JOUR
T1 - SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk
AU - Reitz, Christiane
AU - Tokuhiro, Shinya
AU - Clark, Lorraine N.
AU - Conrad, Christopher
AU - Vonsattel, Jean Paul
AU - Hazrati, Lili Naz
AU - Palotás, András
AU - Lantigua, Raphael
AU - Medrano, Martin
AU - Jiménez-Velázquez, Ivonne Z.
AU - Vardarajan, Badri
AU - Simkin, Irene
AU - Haines, Jonathan L.
AU - Pericak-Vance, Margaret A
AU - Farrer, Lindsay A.
AU - Lee, Joseph H.
AU - Rogaeva, Ekaterina
AU - St. George-Hyslop, Peter
AU - Mayeux, Richard
PY - 2011/1/1
Y1 - 2011/1/1
N2 - 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 underexpression 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.
AB - 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 underexpression 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.
UR - http://www.scopus.com/inward/record.url?scp=79551474326&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79551474326&partnerID=8YFLogxK
U2 - 10.1002/ana.22308
DO - 10.1002/ana.22308
M3 - Article
C2 - 21280075
AN - SCOPUS:79551474326
VL - 69
SP - 47
EP - 64
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 1
ER -