SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

Bettens, Karolien; Brouwers, Nathalie; Engelborghs, Sebastiaan; Deyn, Peter Paul De; Broeckhoven, Christine Van; Sleegers, Kristel

doi:10.1002/humu.20725

Cited by 93 publications

(89 citation statements)

References 14 publications

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“…Indirect analysis of the remaining SNPs gave no nominally significant result at all although a marginal association was found for three SNPs not reported in AlzGene. Although these results still require validation, taken together with previous reports 43,[46][47][48] our data appear to support at least a modest disease association of SORL1, a gene that encodes a product implicated in the regulation of processing and trafficking of the APP.…”

Section: Discussionsupporting

confidence: 77%

Examination of the current top candidate genes for AD in a genome-wide association study

et al. 2009

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With the advent of technologies that allow simultaneous genotyping of thousands of singlenucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.

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Section: Discussionsupporting

confidence: 77%

Examination of the current top candidate genes for AD in a genome-wide association study

et al. 2009

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“…A recent study failed to recapitulate the reduced expression of SORLA in yet another set of post-mortem AD brain samples (Sager et al, 2012), and, therefore, additional studies might be necessary to resolve this issue. Nevertheless, there is strong support for the involvement of SORLA in sporadic AD, which stems from population-based studies that document association of genetic variants of SORL1 (the gene encoding SORLA) with sporadic AD in several ethnicities (Rogaeva et al, 2007;Bettens et al, 2008;Cuenco et al, 2008;Lee et al, 2008;Webster et al, 2008). Cumulative meta-analyses encompassing in excess of 30,000 individuals (Reitz et al, 2011) and genomewide association studies Naj et al, 2011) confirm the association of single nucleotide polymorphisms (SNPs) in SORL1 with AD.…”

Section: Sorla a Neuronal Trafficking Receptor Implicated In Admentioning

confidence: 99%

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Willnow

Andersen

2013

Journal of Cell Science

102

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SummaryExcessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.

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“…A possible link between this receptor and Alzheimer's disease (AD) was suggested by findings that SORLA gene expression is drastically reduced in the brain of patients suffering from the sporadic form of the disease (Scherzer et al, 2004;Dodson et al, 2006). This initial observation was further substantiated by genetic evidence showing an association of SORLA gene variants with risk of AD in several population-based investigations Rogaeva et al, 2007;Bettens et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Reduces Amyloidogenic Processing through Control of SORLA Gene Expression

Rohe

Synowitz²,

Glaß³

et al. 2009

J. Neurosci.

106

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Sorting protein-related receptor with A-type repeats (SORLA) is a major risk factor in cellular processes leading to Alzheimer's disease (AD). It acts as sorting receptor for the amyloid precursor protein (APP) that regulates intracellular trafficking and processing into amyloidogenic-␤ peptides (A␤). Overexpression of SORLA in neurons reduces while inactivation of gene expression (as in knock-out mouse models) accelerates amyloidogenic processing and senile plaque formation. The current study aimed at identifying molecular pathways that control SORLA gene transcription in vivo and that may contribute to low levels of receptor expression in the brain of patients with AD. Using screening approaches in primary neurons, we identified brain-derived neurotrophic factor (BDNF) as a major inducer of Sorla that activates receptor gene transcription through the ERK (extracellular regulated kinase) pathway. In line with a physiological role as regulator of Sorla, expression of the receptor is significantly impaired in mouse models with genetic (Bdnf Ϫ/ Ϫ ) or disease-related loss of BDNF activity in the brain (Huntington's disease). Intriguingly, exogenous application of BDNF reduced A␤ production in primary neurons and in the brain of wild-type mice in vivo, but not in animals genetically deficient for Sorla. These findings demonstrate that the beneficial effects ascribed to BDNF in APP metabolism act through induction of Sorla that encodes a negative regulator of neuronal APP processing.

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SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

Cited by 93 publications

References 14 publications

Examination of the current top candidate genes for AD in a genome-wide association study

Examination of the current top candidate genes for AD in a genome-wide association study

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Brain-Derived Neurotrophic Factor Reduces Amyloidogenic Processing through Control of SORLA Gene Expression

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