Characterization of ATXN1 in APP processing and AD pathogenesis

描述（由申请人提供）：本提案旨在功能表征一种新的阿尔茨海默病（AD）候选基因ATXN1，该基因是在我们最近基于家族的全基因组关联研究（GWAS）中发现的。阿尔茨海默病是一种破坏性的神经退行性疾病，是老年人痴呆的主要原因。大量证据表明，小肽淀粉样蛋白2 （A2）的过度积累是导致AD的主要病理事件。A2是由淀粉样蛋白-2前体蛋白（APP）通过2-和3-分泌酶的连续裂解产生的。通过进一步鉴定和表征影响APP加工的基因，我们希望阐明AD的发病机制。在我们小组最近鉴定新的AD候选基因的GWAS中，我们筛选了1000多个AD家族（5600名受试者），并鉴定了四个新的迟发性AD候选基因，这些基因具有全基因组统计学意义。这不仅是迄今为止最大的基于家族的AD GWAS，也是第一个发现具有全基因组意义的AD新候选基因的GWAS。ataxin-1 （ATXN1）是四个新的AD候选基因之一，是脊髓小脑共济失调1型（SCA1）的疾病基因，SCA1是一种以小脑共济失调和浦肯野细胞丧失为特征的神经退行性疾病。ATXN1经历选择性剪接，有两个主要的mRNA转录变体。先前的一项研究表明，敲除ATXN1的小鼠通过未知的机制表现出严重的认知和行为缺陷。为了确定潜在的机制，在一项独立资助的研究中，我们利用基于细胞的模型表征了ATXN1在APP处理中的作用。我们最近发表的研究结果表明，ATXN1的敲除显著增强了APP的2-分泌酶加工并增加了A2水平。最近，我们的初步研究表明，在ATXN1敲除小鼠中，BACE1水平与APP的2-分泌酶加工一起升高。总之，新出现的证据表明，ATXN1是一种新的AD候选基因，很可能通过功能丧失机制参与AD的发病机制。本研究旨在通过细胞模型、小鼠模型和人类AD脑模型，进一步表征ATXN1调节BACE1水平、APP加工和AD发病机制的分子机制。建议的两年指导支持应该有足够的时间来完成三个目标中的每个目标的第一个子目标，并允许我申请一个独立的职位；三年的独立支持将使我能够完成所有建议的研究。总之，这些旨在功能表征ATXN1的实验不仅将进一步阐明阿尔茨海默病的病因和发病机制，还将为开发治疗和预防阿尔茨海默病的新疗法提供有价值的新见解。

DESCRIPTION (provided by applicant): This proposal is aimed at functionally characterizing a novel Alzheimer's disease (AD) candidate gene, ATXN1, identified in our recent family-based, genome-wide association study (GWAS). AD is a devastating neurodegenerative disease and the primary cause of dementia in the elderly. Considerable evidence suggests that the excessive accumulation of a small peptide, amyloid-2 (A2), is a primary pathological event leading to AD. A2 is produced from the amyloid-2 precursor protein (APP) through sequential cleavage via 2- and 3- secretase. By further identifying and characterizing the genes that influence APP processing we hope to elucidate the pathogenesis of AD. In our group's most recent GWAS to identify novel AD candidate genes, we screened over 1,000 AD families (5,600 subjects) and identified four novel late-onset AD candidate genes that achieved genome-wide statistical significance. This is not only the largest family-based AD GWAS performed to date, but also the first one to identify any AD novel candidate genes with genome-wide significance. One of the four novel AD candidate genes, ataxin-1 (ATXN1) is the disease gene for spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease characterized by ataxia and loss of Purkinje cells in the cerebellum. ATXN1 undergoes alternative splicing and has two primary mRNA transcript variants. A previous study shows that knock-out of ATXN1 mouse displays severe cognitive and behavioral deficits through unknown mechanisms. To identify the underlying mechanism, in an independently funded study, we characterized the roles of ATXN1 in APP processing utilizing cell-based models. Our recently published results showed that knock-down of ATXN1 significantly potentiates 2-secretase processing of APP and increases A2 levels. More recently, our preliminary studies reveal that in ATXN1 knock-out mice BACE1 levels are elevated together with 2-secretase processing of APP. In summary, emerging evidence suggests that ATXN1 is a novel AD candidate gene which contributes to AD pathogenesis, most likely, through a loss-of-function mechanism. This proposal is aimed at further characterizing the molecular mechanisms by which ATXN1 modulates BACE1 levels, APP processing and AD pathogenesis employing cell-based models, mouse models, and human AD brains in three specific aims. The proposed two years of mentored support should allow enough time to complete the first sub- aim in each of the three aims and allow me to apply for an independent position; the three years of independent support will allow me to achieve all the proposed studies. Collectively, the proposed experiments aimed at functionally characterizing ATXN1 will not only further elucidate the etiology and pathogenesis of AD, but also provide valuable new insights into the development of novel therapies for treating and preventing AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease with complex and strong genetic inheritance. Currently there is no cure to stop the progress of AD due to a poor understanding of AD pathogenesis. Here we propose a "translational" study, aimed to functionally characterize a novel AD candidate gene, which may not only provide novel insights into the pathogenesis of AD, but also assist in identifying new therapeutic targets of AD.