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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（30行文字）：