SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk.
SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk.
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DOI：
10.1002/ana.22308
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发表时间：
2011-01
影响因子：
11.2
通讯作者：
Mayeux R
中科院分区：
文献类型：
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作者：
Reitz C;Tokuhiro S;Clark LN;Conrad C;Vonsattel JP;Hazrati LN;Palotás A;Lantigua R;Medrano M;Z Jiménez-Velázquez I;Vardarajan B;Simkin I;Haines JL;Pericak-Vance MA;Farrer LA;Lee JH;Rogaeva E;George-Hyslop PS;Mayeux R
导致淀粉样前体蛋白（APP）与β-分泌酶和γ-分泌酶共定位于同一区室的分选机制在阿尔茨海默病（AD）中Aβ产生的调节中起重要作用。我们和其他人已经报道了分拣蛋白相关受体（SORL 1）的遗传变异增加了AD的风险，SORL 1参与APP的运输，SORL 1的表达不足导致Aβ的过度产生。在这里，我们探讨了其同源物之一，分拣蛋白相关的VPS 10域包含受体1（SORCS 1），在AD中的作用。我们分析了6个独立数据集（2，809例病例和3，482例对照）中16个SORCS 1单核苷酸多态性（SNP）与AD之间的遗传关联。此外，我们在微阵列基因表达和实时聚合酶链反应（RT-PCR）集中比较了AD和对照大脑中受影响和未受影响的大脑区域的SorCS 1表达水平，探讨了显着的SORCS 1-SNP对SorCS 1大脑表达水平的影响，并探讨了常见SorCS 1亚型的抑制和过表达对APP加工和Aβ生成的影响。在所有数据集中，SORCS 1中的遗传变异与AD相关（0.001 < p < 0.049）。此外，SorCS 1影响APP加工。虽然SorCS 1的过表达降低了γ-分泌酶活性和Aβ水平，但SorCS 1的抑制增加了APP的γ-分泌酶加工和Aβ水平。这些数据表明，SORCS 1表达或功能的遗传或获得性变化可能在AD的发病机制中发挥作用。
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. 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. 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. These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.