Characterization of ATXN1 in APP processing and AD pathogenesis

ATXN1 在 APP 加工和 AD 发病机制中的表征

基本信息

批准号：
8334060
负责人：
Can Martin Zhang
金额：
$ 12.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334060
关键词：
Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid 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 Process Protein Precursors 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

项目摘要

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.

脓肿该建议旨在在功能上表征新的阿尔茨海默氏病（AD）候选基因，即在我们最近基于家庭的全基因组协会研究（GWAS）中确定的ATXN1。广告是毁灭性的神经退行性疾病和古老的痴呆症的主要原因。大量证据表明小胡椒的过量积累，淀粉样蛋白 - （a。）是一个主要的病理事件，导致广告。 A是由淀粉样蛋白前体蛋白（APP）通过顺序裂解通过€ - 和€ - 产生的。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的发病机理。在我们小组的最新GWA中，以识别新颖的候选基因，我们筛选了1,000多个广告系列（5,600名受试者），并确定了四个新型的晚期AD候选基因达到了全基因组统计学意义。这不仅是最大的基于家庭的广告GWAS 迄今为止，也是第一个识别任何具有全基因组意义的AD新型候选基因的人。之一四个新型的AD候选基因Ataxin-1（ATXN1）是1型脊髓脑性共济失调的疾病基因（SCA1），一种以共济失调为特征和小脑普林吉细胞丧失的神经退行性疾病。 ATXN1经历替代剪接，并具有两个主要的mRNA转录物变体。先前的研究表明 ATXN1小鼠的敲除显示出严重的认知和行为，通过未知来定义机制。为了确定基本机制，在一项独立资助的研究中，我们表征了 ATXN1在使用基于单元的模型的应用程序处理中的作用。我们最近发布的结果表明 ATXN1的敲除显着潜在的»APP的分泌酶处理并增加了A水平。更多的最近，我们的初步研究表明，在ATXN1敲除，小鼠与 APP的分泌酶处理。总而言之，新兴的证据表明ATXN1是一种新颖的候选人通过功能丧失机制有助于AD发病机理的基因。这个建议旨在进一步表征ATXN1调节BACE1水平的分子机制使用基于细胞的模型，小鼠模型和人类大脑的处理和AD发病机理，三个具体目标。拟议的两年修补支持应允许足够的时间完成第一个子 - 瞄准三个目标中的每个目标，并允许我申请独立职位；三年独立的支持将使我能够实现所有拟议的研究。共同提议的实验旨在在功能上表征ATXN1不仅会进一步阐明AD的病因和发病机理但还为新的治疗和预防广告的新疗法的发展提供了宝贵的新见解。