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Role of Ataxin-1 in BACE1 Expression and Alzheimer's Disease

Ataxin-1 在 BACE1 表达和阿尔茨海默病中的作用

基本信息

批准号：
10390309
负责人：
Jaehong Suh
金额：
$ 41.3万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390309
关键词：
Acute Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Precursor Axon Binding Binding Proteins Biochemical Brain Brain region CAG repeat CRISPR/Cas technology Cell Nucleus Cells Cerebrum Chromatin Culture Media DNA Data Deposition Disease Etiology Family Follow-Up Studies GFI1 gene Gene Expression Gene Mutation Genes Genetic Genetic Determinism Genetic Transcription Genome Gliosis Hippocampus (Brain)Human Impairment Individual Knockout Mice Mammalian Cell Measures Mediating Messenger RNA Meta-Analysis Molecular Movement Mus Mutation Mutation Analysis National Institute of Mental Health Neurodegenerative Disorders Neurons Pathogenesis Pathology Pathway interactions Play Protein Secretion Proteins Proteomics Protocols documentation RNA Recording of previous events Regulation Reporting Research Risk Role Sampling Senile Plaques Site Slice Testing Type 1 Spinocerebellar Ataxia Variant amyloid precursor protein processing ataxin-1 base beta-site APP cleaving enzyme 1 genetic variant genome sequencing genome wide association study inhibitor knock-down loss of function neurogenesis novel novel therapeutics nucleotide analog olfactory bulb prevent promoter secretase transcription factor whole genome

项目摘要

Project Summary Recent efforts to uncover genetic factors responsible for Alzheimer's disease (AD) have identified dozens of associated loci. Among these, our research group previously reported ATXN1 in a family-based AD genome-wide association study. ATXN1 has been otherwise known for to harbor mutations causing spinocerebellar ataxia type 1, a neurodegenerative disease that primarily impairs coordinated movement. In a cell-based study, knockdown of Ataxin-1 gene (ATXN1) expression increased amyloidogenic processing of the amyloid precursor protein (APP) and the secretion of Aβ, the main component of senile plaques in AD brains. In the preliminary examination of Ataxin-1 KO mice, we found Ataxin-1 regulates BACE1 expression, selectively in AD-vulnerable brain regions. In AD mice, depletion of Ataxin-1 increased β-secretase-cleavage of APP, Aβ deposition and gliosis in the cerebrum. Furthermore, Ataxin-1 KO impaired hippocampal neurogenesis and axonal targeting, which are regulated by BACE1. To validate and expand upon these findings, here, we propose to 1. Elucidate the molecular mechanism by which Ataxin-1 regulates BACE1 expression in the brain; 2. Assess the impact of Ataxin-1 loss of function on AD pathogenesis; and 3. Identify and characterize novel AD-associated Ataxin-1 gene variants and/or mutations from AD DNA sample sets. Specifically, for Aim 1, we will first determine whether Ataxin-1 regulates BACE1 mRNA level by affecting its stability or by its transcription. To test this, we will employ acute brain slice cultures of Ataxin-1 KO and WT mice, and examine the differential effects of transcriptional inhibitors on the steady-state level of BACE1 mRNA and also measure newly synthesized BACE1 mRNA incorporating nucleotide analogs in the cultured slices. We will then examine if Ataxin-1-interacting transcriptional factors bind to and regulate BACE1 promoter by ChIP analysis. With regard to Aim 2, we will examine if the increased Aβ plaque load and gliosis are maintained in APP-PS1/ATXN1-KO mice at older age (9 month). To determine if impaired hippocampal neurogenesis and axonal targeting are caused by increased BACE1, we will generate ATXN1 −/−:BACE1 +/− mice and examine if the two deficits are rescued, as compared to ATXN1 −/− mice. Finally, in Aim 3, we will identify ATXN1 mutations/variants that either increase risk or confer protection for AD by analysis of WGS/WES data of NIMH, NIA and ADNI AD DNA sample sets. For the most associated mutations/variants, we will examine their effects on BACE1 expression and APP processing by incorporating them into the genome of human neuronal cells via CRISPR/Cas9 technology. At the completion of the proposed study, we believe we will provide critically needed data addressing the role of Ataxin-1 in regulating BACE1 expression while also facilitating novel therapies aimed at targeting BACE1 to prevent and treat AD.

项目总结