TDP-43, RNA Metabolism, and ALS/FTD Pathology

TDP-43、RNA 代谢和 ALS/FTD 病理学

基本信息

批准号：
8961199
负责人：
Christopher D. Link
金额：
$ 34.95万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8961199
关键词：
Address Affect Age Amyotrophic Lateral Sclerosis Astrocytes Attention Binding Proteins Biological Assay Biological Models C9ORF72 Caenorhabditis elegans Cell Culture Techniques Cells Complement Cytoplasmic Inclusion DNA Sequence Alteration Data Defect Deposition Dipeptides Disease Double-Stranded RNA Endogenous Retroviruses Familial Amyotrophic Lateral Sclerosis Fibroblasts Frontotemporal Dementia Functional disorder Gene Expression Profile Genes Goals Human In Situ Hybridization In Vitro Lead Link Measures Metabolism Modeling Molecular Motor Neurons Mutate Mutation Neurodegenerative Disorders Neuroglia Neurons Nuclear Orthologous Gene Pathology Patients Play Process Production Proteins RNA Processing Research Personnel Retrotransposon Ribosomal RNA Risk Factors Role Sampling Structure TDP-1 Testing Tissues Transcript Translations adapter protein base deep sequencing immunocytochemistry in vivo knock-down loss of function neuroinflammation novel prevent protein TDP-43 protein function public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Dramatic advances have been made in recent years in the identification of genes that cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two closely related neurodegenerative diseases. This includes at least three RNA binding proteins (TDP-43, FUS and MATR3) and a hexanucleotide expansion in RNA transcripts of the C9orf72 gene. These findings have focused much attention on understanding how changes in RNA metabolism might underlie these diseases. Although most cases of ALS are sporadic (no obvious familial inheritance), in almost all cases the TDP-43 protein is found in cytoplasmic inclusions in affected motor neurons, suggesting the functions of this protein are broadly relevant to ALS. We have characterized the functions of TDP-43 in a model system (C. elegans) and cell culture, and discovered that loss of this protein results in accumulation of double-stranded RNA (dsRNA) and abnormal processing of ribosomal RNA. The goal of this proposal is to determine if these changes in the metabolism of RNA play a role in ALS/FTD pathology. We will investigate the molecular mechanisms by which TDP-43 limits dsRNA, and seek to determine if loss of FUS and MATR3, or expression of the C9orf72 hexanucleotide expansion, have similar effects on RNA metabolism. The disease-associated cytoplasmic redistribution of TDP-43 will also be investigated, particularly in response to expression of the C9orf72 hexanucleotide expansion and the associated production of aggregation-prone poly-dipeptides. These studies will employ RNA interference, genetic mutations, immunocytochemistry, in situ hybridization, and deep sequencing to globally characterize RNAs (the transcriptome), using both human cell culture and C. elegans models. We will test the disease relevance of our findings by extending these studies to patient cells (fibroblasts and reprogrammed neurons) as well as pathological samples. In particular, we will test the hypothesis that the RNA changes we have identified may play a role in the neuroinflammation and astroglial dysfunction that has been implicated in ALS pathology.

描述（申请人证明）：近年来在引起家族性侧面硬化症（ALS）和额叶痴呆症（FTD）的基因鉴定方面取得了巨大进展，两种近似相关的神经退行性疾病（TDP-43，FUS和MATR3，FUS和MATR3和MATR3））和C9orf72基因的RNA转录中的六核苷酸。受影响的运动神经元中的夹杂物与ALS广泛相关。为了确定RNA代谢的变化是否在ALS/FTD病理学中起ROLEE的作用。对RNA代谢有相似的作用。（转录组），使用人类培养物和秀丽隐杆线虫模型，将这些研究扩展到患者细胞（纤维细胞和重编程的神经元）以及病理样本。在神经炎症和星形胶质功能障碍中发挥作用。