Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion

C9orf72 六核苷酸重复扩增引发 ALS/FTD 致病级联的分子基础

基本信息

批准号：
10512236
负责人：
Jiou Wang
金额：
$ 62.76万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512236
关键词：
Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Binding Biochemical Brain C9ORF72 Cells Chromatin Clinical DAXX gene DNA DNA Binding DNA Repeat Expansion DNA-Binding Proteins Defect Dementia Disease Elderly Elements Epigenetic Process Equilibrium Etiology Feedback Foundations Frontotemporal Dementia Gene Expression Gene Expression Regulation Genes Genetic Genetic Diseases Genetic Polymorphism Genetic study Genome Genomics Goals Human Genome Huntington Disease Hybrids Intervention Knowledge Lead Light Link Mediating Microsatellite Repeats Modeling Molecular Molecular Genetics Motor Neurons Mutation Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Nuclear Nuclear Protein Nucleotides Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phase Phenotype Phosphotransferases Physical condensation Process Proteins Public Health RNA Regulation Reporting Research Role Series Short Tandem Repeat Signal Transduction Societies Stress Structure Temporal Lobe Toxic effect Transcriptional Regulation Translations Untranslated RNA Work base biological adaptation to stress chromatin remodeling effective therapy frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis gain of function genetic approach genome wide association study genome-wide infancy insight loss of function nervous system disorder neurotoxicity novel novel strategies novel therapeutic intervention sporadic amyotrophic lateral sclerosis theories

项目摘要

Project Summary Nucleotide repeat elements, including microsatellites or short tandem repeats, are common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to over 50 different types of genetic disorders, primarily neurological and neuromuscular disorders. Our understanding of how these repeat elements in the human genome cause diseases is still in its infancy. A hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72 hexanucleotide repeat expansion represents the most common genetic cause of both familial and sporadic ALS. FTD is characterized by degeneration of the frontal and temporal lobes of the brain and is the second-most common type of dementia in people older than 65; the C9orf72 hexanucleotide repeat expansion is also the most common genetic cause of FTD. This repeat expansion is also found to contribute to Alzheimer’s disease and Huntington’s disease. To help relieve the public health burden associated with these diseases, it is important to understand the mechanisms underlying their pathogenesis. Multiple hypotheses exist to explain the pathogenic mechanisms underlying C9orf72-linked ALS/FTD. The goal of the proposed project is to elucidate novel mechanisms through which the C9orf72 hexanucleotide repeat expansion leads to molecular defects and neuronal toxicity, focusing on gain-of-function mechanisms. The specific aims are to identify previously unknown pathogenic cascades initiated by the C9orf72 hexanucleotide repeat expansion. These novel pathogenic cascades include, but are not limited to, RNA toxicity and non-canonical translation products resulting from the C9orf72 hexanucleotide repeat expansion. We propose a series of fundamental studies that combine biochemical, molecular, and genetic approaches to shed light on the novel pathways leading to ALS/FTD pathogenesis and to identify potential intervention strategies. Successful completion of the project is expected to provide insights into fundamental mechanisms of neurodegeneration in ALS/FTD that may ultimately lead to novel approaches for treating ALS/FTD and other relevant neurodegenerative diseases.

项目摘要核苷酸重复元素，包括微卫星或短串联重复，是在真核基因组中常见。短核苷酸重复的扩展已与超过50种不同类型的遗传疾病，原发性神经和神经肌肉疾病。我们对人类基因组中这些重复元素引起疾病的理解仍然是在起步期。在C9ORF72基因的非编码区域中的六核苷酸重复扩展具有与神经退行性疾病肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）。 ALS的特征是运动神经元的丧失，而C9orf72 六核苷酸重复膨胀代表了两个家族的最常见遗传原因和零星的ALS。 FTD的特征是额叶和临时爱的变性大脑是65岁以上患者的第二常见痴呆类型； C9orf72 六核苷酸重复膨胀也是FTD的最常见遗传原因。重复还发现扩张会导致阿尔茨海默氏病和亨廷顿氏病。提供帮助减轻与这些疾病相关的公共卫生烧伤，了解其发病机理的基础机制。存在多种假设来解释致病性 C9ORF72链接ALS/FTD的机制。拟议项目的目标是阐明了C9ORF72六核苷酸重复膨胀引线的新型机制分子缺陷和神经元毒性，重点是功能获取机制。这具体目的是确定C9orf72发起的先前未知的病原级联六核苷酸重复扩展。这些新型的致病级联反应包括但不限到由C9orf72产生的RNA毒性和非典型翻译产物六核苷酸重复扩展。我们提出了一系列基本研究，结合了生化，分子和遗传学方法，以阐明新的途径，导致 ALS/FTD发病机理并确定潜在的干预策略。成功完成预计该项目将提供有关基本机制的见解 ALS/FTD中的神经变性可能最终导致治疗的新方法 ALS/FTD和其他相关神经退行性疾病。