Sorl1 as an Alzheimer's disease predisposition gene?
ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) epsilon4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval.
Article: Genetics of Alzheimer's disease.[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) represents the main form of dementia, and is a major public health problem. Despite intensive research efforts, current treatments have only marginal symptomatic benefits and there are no effective disease-modifying or preventive interventions. AD has a strong genetic component, so much research in AD has focused on identifying genetic causes and risk factors. This chapter will cover genetic discoveries in AD and their consequences in terms of improved knowledge regarding the disease and the identification of biomarkers and drug targets. First, we will discuss the study of the rare early-onset, autosomal dominant forms of AD that led to the discovery of mutations in three major genes, APP, PSEN1, and PSEN2. These discoveries have shaped our current understanding of the pathophysiology and natural history of AD as well as the development of therapeutic targets and the design of clinical trials. Then, we will explore linkage analysis and candidate gene approaches, which identified variants in Apolipoprotein E (APOE) as the major genetic risk factor for late-onset, "sporadic" forms of AD (LOAD), but failed to robustly identify other genetic risk factors, with the exception of variants in SORL1. The main focus of this chapter will be on recent genome-wide association studies that have successfully identified common genetic variations at over 20 loci associated with LOAD outside of the APOE locus. These loci are in or near-novel AD genes including BIN1, CR1, CLU, phosphatidylinositol-binding clathrin assembly protein (PICALM), CD33, EPHA1, MS4A4/MS4A6, ABCA7, CD2AP, SORL1, HLA-DRB5/DRB1, PTK2B, SLC24A4-RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, and TRIP4 and each has small effects on risk of AD (relative risks of 1.1-1.3). Finally, we will touch upon the ongoing effort to identify less frequent and rare variants through whole exome and whole genome sequencing. This effort has identified two novel genes, TREM2 and PLD3, and shown a role for APP in LOAD. The identification of these recently identified genes has implicated previously unsuspected biological pathways in the pathophysiology of AD.
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ABSTRACT: The retromer coat complex is a vital component of the intracellular trafficking mechanism sorting cargo from the endosomes to the trans-Golgi network or to the cell surface. In recent years, genes encoding components of the retromer coat complex and members of the vacuolar protein sorting 10 (Vps10) family of receptors, which play pleiotropic functions in protein trafficking and intracellular/intercellular signaling in neuronal and non-neuronal cells and are primary cargos of the retromer complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and frontotemporal lobar degeneration. In addition to their functions in protein trafficking, the members of the Vps10 receptor family (sortilin, SorL1, SorCS1, SorCS2, and SorCS3) modulate neurotrophic signaling pathways. Both sortilin and SorCS2 act as cell surface receptors to mediate acute responses to proneurotrophins. In addition, sortilin can modulate the intracellular response to brain-derived neurotrophic factor (BDNF) by direct control of BDNF levels and regulating anterograde trafficking of Trk receptors to the synapse. This review article summarizes the emerging data from this rapidly growing field of intracellular trafficking signaling in the pathogenesis of neurodegeneration.Molecular Genetics and Genomics 10/2014; 290(2). DOI:10.1007/s00438-014-0939-9 · 2.83 Impact Factor
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ABSTRACT: Late-onset Alzheimer's Disease (LOAD) is a common neurodegenerative disease, and the two well identified pathological hallmarks of LOAD are senile plaques formed from amyloid β peptides (Aβ) and neurofibrillary tangles (NFTs) consisting of hyperphorylated tau protein. The neuronal Sortilin-related Receptor (SORL1) is involved in the processing and trafficking of amyloid precursor protein (APP) into recycling pathways, thus influencing Aβ generation and by this AD pathology. To explore the relationship between the single nucleotide polymorphism (SNP) of the SORL1 SNP 19 rs2070045 and LOAD, a case-control study was conducted in a Chinese Han cohort including 77 LOAD patients and 100 control participants. This SNP 19 rs2070045 was genotyped with a polymerase chain reaction-restriction fragment length polymorphism, (PCR-RFLP) method. The association was revealed between the polymorphism of SNP 19 rs2070045 (T/T, T/G, G/G) and the risk of LOAD. The results of this study indicated that the T allele (T/G+T/T) of SNP 19 rs2070045 was successful in exerting obvious influence in LOAD patients (χ2=4.884, P=0.027<0.05). However, there is no sufficient evidence to prove that the T allele of SNP 19 rs2070045 is associated with ɛ4 allele of ApoE gene in LOAD patients (χ2=0.771, P=0.380>0.05).Neuroscience Letters 12/2013; DOI:10.1016/j.neulet.2013.11.042 · 2.06 Impact Factor