Identifying and understanding the role of repeat RNAs and RAN proteins in Alzheimer's disease

识别和理解重复 RNA 和 RAN 蛋白在阿尔茨海默病中的作用

基本信息

批准号：
10833734
负责人：
Lien Nguyen
金额：
$ 24.9万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10833734
关键词：
Acceleration Activities of Daily Living Affect Age Years Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Autophagocytosis Autopsy Biological Assay Biology Brain Brain region C-terminal C9ORF72 CASP8 gene Clinical Complex DNA Probes Data Dementia Detection Disease Double-Stranded RNA Early Onset Familial Alzheimer&apos s Disease Frequencies Frontotemporal Dementia General Population Genes Genetic Genomic DNA Grant Heterogeneity High-Throughput Nucleotide Sequencing Human Human Genome Impaired cognition Induced pluripotent stem cell derived neurons Inherited Late Onset Alzheimer Disease Link Methods Modeling Molecular Mus Mutation Neurodegenerative Disorders Neurofibrillary Tangles Neuromuscular Diseases Pathogenicity Pathologic Pathology Pathway interactions Patients Penetrance Persons Polymers Predisposition Proteins RNA Repetitive Sequence Reporting Risk Factors Role Sampling Senile Plaques Southern Blotting Stress Techniques Testing Text Therapeutic Tissues Toxic effect Toxicity Tests Translations United States Variant abeta accumulation abeta deposition abeta toxicity apolipoprotein E-4 behavioral impairment disorder risk effective therapy extracellular follow-up frontotemporal lobar dementia amyotrophic lateral sclerosis gain of function hyperphosphorylated tau individual patient insight multicatalytic endopeptidase complex neuron loss novel novel therapeutics presenilin-1 presenilin-2 protein aggregation proteostasis ran GTP-Binding Protein rapid technique synaptic function tau Proteins tau-1 therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT (30 lines of text): Alzheimer’s disease, the most common form of dementia, is characterized by cognitive decline and impairment of behavioral and functional abilities. Approximate 5.8 million people in the United States are affected by Alzheimer’s disease (AD) and this number is anticipated to triple by 2050. While mutations in amyloid precursor protein (APP) and presenillin (PSEN1 and PSEN2) are known to cause familial early onset AD and the APOE4 variant is a well-known disease risk factor, the genetic contributions to the majority of late onset AD cases are not clear. Additionally, while the accumulation of Aβ plaques and hyperphosphorylated tau are considered to be hallmark features of AD cases, Aβ plaques and tau tangles do not fully explain the clinical features and heterogeneity found in AD patients. The identification of the C9orf72 GGGGCC hexanucleotide repeat expansion as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia raises an intriguing question whether unidentified repeat expansion mutations contribute to other form of dementia including AD. Additionally, similarities in disease pathology are observed between AD and patients with repeat expansion disorders. These similarities include the accumulation of abnormal proteins, neuronal loss in affected brain regions, and the involvement of stress in worsening disease. While repetitive elements account for a large portion of the human genome, the detection repeat-expansion mutations, especially GC-rich repeat expansions, is challenging. To overcome the difficulties in identifying repeat expansion mutations, I have developed a novel dCas9-based repeat pull-down method (dCas9READ) that allows the isolation of repeat expansion mutations directly from the genomic DNA of individual patients. The objective of this proposal is to test the hypothesis that novel repeat expansion mutations contribute to late onset AD and their repeat containing RNA and RAN products are toxic and contribute to AD pathology. I am excited to report that in an initial screen, 17.5% of human AD autopsy cases tested were positive for RAN protein aggregates and RNA foci. In this grant, I will follow-up on these exciting preliminary data and test this hypothesis that novel repeat expansion mutations contribute to AD in the following specific aims: Aim 1) Will develop a novel dCas9-based technique for rapidly identifying repeat expansions. Aim 2) Will test the hypothesis that novel repeat expansions mutations are present at higher frequencies in late onset AD vs. control samples. Aim 3) Will test the hypothesis that novel repeat expansion mutations are toxic and contribute to AD pathology.

项目摘要/摘要（文本30行）：阿尔茨海默氏病是最常见的痴呆形式，其特征是认知能力下降和障碍行为和功能能力。美国约有580万人受到影响阿尔茨海默氏病（AD）和该数字预计到2050年将三倍。淀粉样蛋白突变已知前体蛋白（APP）和Presenillin（PSEN1和PSEN2）会引起家庭早期发作AD和 APOE4变体是众所周知的疾病风险因素，是对最近发作大多数的遗传贡献广告案件尚不清楚。另外，虽然Aβ斑块和高磷酸化的tau的积累是 Aβ斑块和tau缠结认为是AD病例的标志性特征，无法完全解释临床 AD患者发现的特征和异质性。 C9ORF72 GGGGCC六核苷酸的识别重复膨胀是肌萎缩性侧硬化和额颞叶的最常见遗传原因痴呆提出了一个有趣的问题痴呆症的形式包括广告。此外，在AD和重复扩张障碍的患者。这些相似之处包括异常蛋白质的积累，受影响的大脑区域的神经元丧失以及压力参与令人担忧的疾病。虽然重复元素解释了人类基因组的很大一部分，检测重复膨胀突变，尤其是GC丰富的重复扩展，是挑战。克服识别重复的困难扩展突变，我已经开发了一种基于DCAS9的新型重复下拉方法（DCAS9READ）允许直接从单个患者的基因组DNA直接分离重复扩张突变。这该提议的目的是检验以下假设：新型重复扩展突变有助于迟到发作AD及其重复包含RNA和RAN产品是有毒的，并有助于AD病理学。我是兴奋地报告说，在初始屏幕中，测试的人类AD尸检病例中有17.5％的RAN为阳性蛋白质聚集体和RNA焦点。在这笔赠款中，我将跟进这些令人兴奋的初步数据并进行测试假设新型重复扩展突变在以下特定目的中有助于AD：AIM 1）开发一种基于DCAS9的新型技术，用于快速识别重复扩展。 AIM 2）将测试假设新型重复扩展突变在晚期AD VS中存在较高的频率。控制样品。 AIM 3）将检验以下假设：新型重复扩展突变有毒并有助于进行广告病理学。