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：
10659232
负责人：
Jiou Wang
金额：
$ 62.1万
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/10659232
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 EIF-2alpha Elderly Elements Epigenetic Process Equilibrium Etiology Expanded DNA Repeat 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 Link Mediating Microsatellite Repeats Modeling Molecular 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 c9FTD/ALS 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.

项目概要核苷酸重复元件，包括微卫星或短串联重复序列，短核苷酸重复的扩展与真核基因组中常见。超过 50 种不同类型的遗传性疾病，主要是神经系统和神经肌肉疾病。我们对人类基因组中这些重复元件如何导致疾病的理解仍然不明确 C9orf72 基因非编码区的六核苷酸重复扩增已处于起步阶段。与神经退行性疾病肌萎缩侧索硬化症（ALS）有关额颞叶痴呆 (FTD) 的特点是运动神经元和 C9orf72 的丧失。六核苷酸重复扩增代表了两个家族性遗传病最常见的遗传原因散发性 ALS 的特点是额叶和颞叶退化。 C9orf72 是 65 岁以上人群中第二常见的痴呆症类型；六核苷酸重复扩增也是 FTD 最常见的遗传原因。研究还发现，扩张对阿尔茨海默病和亨廷顿舞蹈病有帮助。减轻与这些疾病相关的公共卫生负担，重要的是要了解存在多种假设来解释其发病机制。 C9orf72 相关 ALS/FTD 的潜在机制拟议项目的目标是阐明 C9orf72 六核苷酸重复扩增导致的新机制分子缺陷和神经毒性，重点关注功能获得机制。具体目标是识别由 C9orf72 引发的先前未知的致病级联反应这些新的致病级联包括但不限于六核苷酸重复扩增。 C9orf72 产生的 RNA 毒性和非规范翻译产物我们提出了一系列结合六核苷酸重复扩展的基础研究。生物化学、分子和遗传学方法揭示了导致的新途径 ALS/FTD 发病机制并确定潜在的干预策略成功完成。该项目的研究预计将提供对基本机制的见解 ALS/FTD 中的神经退行性疾病最终可能会带来新的治疗方法 ALS/FTD 和其他相关的神经退行性疾病。