Article

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

University of Florence, Florens, Tuscany, Italy
Nature Genetics (Impact Factor: 29.65). 03/2007; 39(2):168-77. DOI: 10.1038/ng1943
Source: PubMed

ABSTRACT The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

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Available from: Joseph H Lee, Jul 30, 2015
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    • "Genome wide association studies (GWAS) continuously provide new risk genes for AD, a growing number of which are SEALE components (Source: www.alzgene.org). One such protein is the neuronal sortilin-related receptor, SORL1, which has been shown to reduce the amyloidogenic processing of APP by redirecting internalised APP away from endosomal organelles containing b-secretase [66]. SorL1 also mediates the cellular uptake of Ab bound to ApoE [67], adding further weight to its neuroprotective function. "
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    ABSTRACT: For over a century, researchers have observed similar neurodegenerative hallmarks in brains of people affected by rare early-onset lysosomal storage diseases and late-onset neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increasing evidence suggests these apparently disparate diseases share a common underlying feature, namely, a dysfunctional clearance of cellular cargo through the secretory-endosomal-autophagic-lysosomal-exocytic (SEALE) network. By providing examples of rare and common neurodegenerative diseases known to have pathologically altered cargo flux through the SEALE network, we explore the unifying hypothesis that impaired catabolism or exocytosis of SEALE cargo, places a burden of stress on neurons that initiates pathogenesis. We also describe how a growing understanding of genetic, epigenetic and age-related modifications of the SEALE network, has inspired a number of novel disease-modifying therapeutic approaches aimed at alleviating SEALE storage and providing therapeutic benefit to people affected by these devastating diseases across the age spectrum. Copyright © 2014 Elsevier Ltd. All rights reserved.
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    • "M, major allele; m, minor allele; MM, major allele homozygote; Mm, heterozygote; mm, minor allele homozygote; ref, reference; * p < 0.05; * * p < 0.01; * * * p < 0.001. a Rogaeva's SNP ID [2]. "
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    • "Similarly , proteins of the GGA family have been shown to traffic BACE1 from endosomes to the Golgi, and their depletion led to increased amyloidogenic processing of APP (He et al., 2005; Tesco et al., 2007; von Arnim et al., 2006). Although APP is known to be routed from endosomes to Golgi via the retromer and retromer-associated proteins including SORL1 and VPS26 (Andersen et al., 2005; Morel et al., 2013; Small and Gandy, 2006; Rogaeva et al., 2007; Small et al., 2005; Siegenthaler and Rajendran, 2012), nothing much is known about BACE1 recycling from endosomes. A better understanding of the specific trafficking mechanisms involved in Ab production will thus provide further insights into disease pathogenesis and potentially provide novel therapeutic strategies for treating this currently untreatable disease. "
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    ABSTRACT: Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides, which are generated from amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aβ levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aβ production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled β-secretase endosomal recycling to the plasma membrane and thus affected Aβ production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aβ levels and show how systems biology approaches can unravel the molecular complexity underlying AD.
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