Characterization of ATXN1 in APP processing and AD pathogenesis

ATXN1 在 APP 加工和 AD 发病机制中的表征

• 批准号: 8754100
• 负责人: Can Martin Zhang
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754100
• 关键词: Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Animal Model; Ataxia; Behavioral; Biochemical; Biological; Brain; Candidate Disease Gene; Cell model; Cells; Cerebellum; Cognition; Cognitive; Complex; Data; Dementia; Deposition; Deterioration; Development; Disease; Down-Regulation; Elderly; Etiology; Event; Exhibits; Family; Funding; Gene Expression Regulation; Generations; Genes; Genetic; Human; Knock-out; Knockout Mice; Late Onset Alzheimer Disease; Lead; Link; Mentors; Messenger RNA; Meta-Analysis; Metabolism; Modeling; Molecular; Motor Neurons; Mus; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Play; Positioning Attribute; Publishing; Purkinje Cells; RNA; RNA Splicing; Risk; Role; Single Nucleotide Polymorphism; Time; Tissues; Transcript; Transgenic Mice; Transgenic Organisms; Type 1 Spinocerebellar Ataxia; Variant; amyloid peptide; amyloid precursor protein processing; ataxin-1; base; beta-site APP cleaving enzyme 1; genetic variant; genome wide association study; genome-wide; insight; knock-down; loss of function; mouse model; new therapeutic target; novel; prevent; protein degradation; research study; secretase; translational study

ABSATRACT 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-¿ (A¿), is a primary pathological event leading to AD. A¿ is produced from the amyloid-¿ precursor protein (APP) through sequential cleavage via ¿- and ¿- 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 ¿-secretase processing of APP and increases A¿ levels. More recently, our preliminary studies reveal that in ATXN1 knock-out mice BACE1 levels are elevated together with ¿-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.

阿萨特拉克 这项提议旨在对一种新的阿尔茨海默病(AD)候选基因进行功能表征， ATXN1，在我们最近的基于家族的全基因组关联研究(GWAS)中确定。广告是毁灭性的 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(A)的过度积聚是导致 广告。淀粉样前体蛋白(APP)通过-和-的顺序切割产生α-。 分泌酶。通过进一步识别和表征影响应用程序处理的基因，我们希望 阐明AD的发病机制。在我们小组最近一次发现AD候选基因的最新研究中，我们 筛选了1,000多个AD家系(5,600名受试者)，并确定了四个新的晚发性AD候选基因 实现了全基因组的统计意义。这不仅是执行的最大的基于系列的AD GWAS 到目前为止，也是第一个发现具有全基因组意义的AD新候选基因的人。其中之一 四个新的AD候选基因ataxin-1(ATXN1)是脊髓小脑性共济失调1型的致病基因 (SCA1)是一种神经退行性疾病，特征是小脑中的浦肯野细胞丢失和共济失调。 ATXN1经历选择性剪接，有两个主要的mRNA转录变异体。先前的一项研究表明 敲除的ATXN1小鼠在未知的情况下表现出严重的认知和行为缺陷 机制。为了确定潜在的机制，在一项独立资助的研究中，我们描述了 ATXN1在利用基于细胞的模型的应用程序处理中的作用。我们最近公布的结果表明， ATXN1基因的敲除显著增强了APP的分泌酶处理，并增加了Aβ水平。更多 最近，我们的初步研究表明，在ATXN1基因敲除小鼠中，BACE1水平与 ？-APP的内分泌处理。总之，新出现的证据表明，ATXN1是一种新的AD候选基因 参与AD发病的基因，很可能是通过功能丧失机制。这项建议 旨在进一步表征ATXN1调节BACE1水平的分子机制，APP 使用基于细胞的模型、小鼠模型和人类AD大脑的三种处理和AD发病机制 明确的目标。拟议的两年指导支持应该有足够的时间完成第一个子项目- 瞄准这三个目标中的每一个，并允许我申请一个独立的职位； 独立的支持将使我能够完成所有拟议的研究。总的来说，拟议的实验 针对ATXN1的功能特征，不仅将进一步阐明AD的病因和发病机制， 也为开发治疗和预防AD的新疗法提供了有价值的新见解。