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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件，包括微卫星或短串联重复序列，在真核生物基因组中很常见短核苷酸重复序列的扩增与超过50种不同类型的遗传疾病，主要是神经和神经肌肉疾病。我们对人类基因组中这些重复元件如何引起疾病的理解仍然是处于萌芽阶段。C9 orf 72基因非编码区的六核苷酸重复扩增，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）。ALS的特征在于运动神经元的损失，并且C9 orf 72 六核苷酸重复序列扩增代表了两种家族性疾病最常见的遗传原因。和偶发性肌萎缩性侧索硬化症FTD的特征是额叶和颞叶变性，大脑，是65岁以上人群中第二常见的痴呆症类型; C9 orf 72 六核苷酸重复扩增也是FTD最常见的遗传原因。该重复还发现这种扩张有助于阿尔茨海默氏病和亨廷顿氏病。帮助为了减轻与这些疾病相关的公共卫生负担，了解其发病机制。存在多种假说来解释致病性 C9 orf 72相关ALS/FTD的潜在机制。拟议项目的目标是阐明C9 orf 72六核苷酸重复扩增导致分子缺陷和神经毒性，重点是获得功能的机制。的具体的目的是确定以前未知的致病级联启动的C9 orf 72 六核苷酸重复扩增。这些新的致病级联反应包括但不限于 RNA毒性和C9 orf 72产生的非经典翻译产物六核苷酸重复扩增。我们提出了一系列的基础研究，联合收割机生物化学、分子和遗传学方法来阐明导致 ALS/FTD发病机制，并确定潜在的干预策略。成功完成预计该项目将提供深入了解基本机制， ALS/FTD中的神经变性，最终可能导致治疗ALS/FTD的新方法。 ALS/FTD和其他相关神经退行性疾病。