Identification of Alzheimer disease associated variants in genes that regulate retromer function
Identifieur interne : 001217 ( Main/Exploration ); précédent : 001216; suivant : 001218Identification of Alzheimer disease associated variants in genes that regulate retromer function
Auteurs : Badri N. Vardarajan [États-Unis] ; Sophia Y. Bruesegem [Royaume-Uni] ; Michael E. Harbour [Royaume-Uni] ; Peter St. George-Hyslop [Royaume-Uni, Canada] ; Matthew N. J. Seaman [Royaume-Uni] ; Lindsay A. Farrer [États-Unis]Source :
- Neurobiology of Aging [ 0197-4580 ] ; 2012.
Abstract
The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic Aβ peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediator of APP localization is SorL1 – a membrane protein that has been genetically linked to AD. The retromer complex is a conserved protein complex required for endosome-to-Golgi retrieval of a number of physiologically important membrane proteins including SorL1. Based on the prior suggestion that endocytosis and retromer sorting pathways might be involved, we hypothesized that variants in other genes in this pathway might also modulate AD risk. Genetic association of AD with 451 polymorphisms in 15 genes encoding retromer or retromer-associated proteins was tested in a Caucasian sample of 8,309 AD cases and 7,366 cognitively normal elders using individual SNP and gene-based tests. We obtained significant evidence of association with
Url:
DOI: 10.1016/j.neurobiolaging.2012.04.020
PubMed: 22673115
PubMed Central: 3391348
Affiliations:
- Canada, Royaume-Uni, États-Unis
- Angleterre, Angleterre de l'Est, Massachusetts, Ontario
- Cambridge, Toronto
- Université de Cambridge, Université de Toronto
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p id="P2">The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic Aβ peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediator of APP localization is SorL1 – a membrane protein that has been genetically linked to AD. The retromer complex is a conserved protein complex required for endosome-to-Golgi retrieval of a number of physiologically important membrane proteins including SorL1. Based on the prior suggestion that endocytosis and retromer sorting pathways might be involved, we hypothesized that variants in other genes in this pathway might also modulate AD risk. Genetic association of AD with 451 polymorphisms in 15 genes encoding retromer or retromer-associated proteins was tested in a Caucasian sample of 8,309 AD cases and 7,366 cognitively normal elders using individual SNP and gene-based tests. We obtained significant evidence of association with <italic>KIAA1033</italic>
(Paris p = 0.025), <italic>SNX1</italic>
(Paris p =0.035), <italic>SNX3</italic>
(p = 0.0057) and <italic>RAB7A</italic>
(Paris p = 0.018). Ten <italic>KIAA1033</italic>
SNPs were also significantly associated with AD in a group of African Americans (513 AD cases, 504 controls). Findings with four significant <italic>SNX3</italic>
SNPs in the discovery sample were replicated in a community-based sample of Israeli-Arabs (124 AD cases, 142 controls). We show that Snx3 and Rab7A proteins interact with the cargo-selective retromer complex through independent mechanisms to regulate the membrane association of retromer and thereby are key mediators of retromer function. These data implicate additional AD risk genes in the retromer pathway and formally demonstrate a direct link between the activity of the retromer complex and the pathogenesis of AD.</p>
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