Shared and disparate genomic features of TDP-43 proteinopathies

TDP-43 蛋白病共有和不同的基因组特征

基本信息

批准号：
10537655
负责人：
Barbara Elizabeth Spencer
金额：
$ 6.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-08-19 至 2025-08-18
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537655
关键词：
Amyotrophic Lateral Sclerosis Attenuated Automobile Driving Autopsy Behavioral Bioinformatics Biological Brain C9ORF72 Characteristics Clinical Cognitive Complex DNA Binding DNA Sequence Alteration Data Dementia Development Disease Family Foundations Frontotemporal Lobar Degenerations Functional disorder Gene Expression Genes Genetic Genetic Variation Genomics Genotype Heterogeneity Immunohistochemistry Impaired cognition Individual Link Measures Medical Genetics Mentorship Molecular Motor Cortex Motor Neurons Mutation Nerve Degeneration Neurodegenerative Disorders Pathologic Pathology Pattern Phenotype Predisposition Quantitative Trait Loci Research Support Risk Sampling Signal Transduction Single Nucleotide Polymorphism Syndrome Temporal Lobe Testing Tissue Sample Tissue-Specific Gene Expression Tissues Training Transcriptional Regulation Variant Weight Work behavioral impairment case control causal variant cell type clinical heterogeneity differential expression digital disorder risk experience frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis functional genomics genetic association genetic risk factor genetic variant genome wide association study genomic locus insight neuromuscular neuropathology novel novel strategies polygenic risk score protein TDP-43 regional difference risk variant statistics superoxide dismutase 1 therapeutic development therapeutic target trait transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract TAR DNA-binding ~43kDa (TDP-43) inclusions are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Despite shared pathological features, ALS and FTLD-TDP can present with heterogenous clinical features including cognitive/behavioral impairments (i.e., FTLD-TDP), motor neuron dysfunction (i.e., ALS), or both (i.e., ALS-FTD). Moreover, certain genetic mutations typically only result in ALS or FTLD-TDP, but other mutations can cause FLTD-TDP and/or ALS within the same family. Together, the shared and disparate pathological, clinical, and genetic features of FTLD-TDP, ALS, and ALS-FTD support the notion that they are part of a clinicopathologic spectrum. However, the vast majority of ALS and FTLD-TDP cases are considered sporadic and have no known causal mutation. The underlying molecular mechanisms that contribute to the observed clinical heterogeneity across sporadic TDP-43 proteinopathies are not well understood. Supporting evidence for a genetic component to sporadic cases, common genetic variants have been associated with disease risk for either ALS or FTLD-TDP. However, combined studies across TDP-43 proteinopathies are rare. Thus, the extent to which risk alleles are shared or disparate across these phenotypes is unclear. While there is mounting evidence of shared genetic factors that explain the biological mechanisms that drive susceptibility to both diseases, considerably less effort has focused on the disparate genetic features across TDP-43 proteinopathies. Identifying disparate variants may contribute to our understanding of disease-specific drivers. The first aim of this proposal is to identify both the shared and disparate genomic features that drive individual-level cognitive/behavioral and/or neuromuscular presentations of these syndromes. TDP-43 pathology and neurodegeneration are observed in characteristic neuroanatomical regions that correlate with the clinical presentations of ALS and FTLD-TDP, but it is unclear what contributes to this regional selective vulnerability. Previous work has demonstrated clear regional differences in gene expression within the same individuals. Gene expression quantitative trait loci analyses can identify genomic loci that explain variation in gene expression. However, these associations are highly tissue and cell type specific, which may obscure important differences. This is especially true within neurodegenerative disorders, as observed gene expression differences may reflect cell type composition differences rather than true transcriptional regulation. The second aim of this proposal is to investigate genetic contributions to regionally specific differential gene expression, including cell type specific expression, in ALS and FTLD-TDP. Overall, this proposal leverages genotype and transcriptomic approaches to understand molecular contributions of regional selective vulnerability in ALS and FTLD-TDP. In disentangling this heterogeneity, it may be possible to inform efforts to develop therapeutic targets that attenuate the course of these neurodegenerative diseases.

项目概要/摘要 TAR DNA 结合 ~43kDa (TDP-43) 内含物是额颞叶的病理标志 TDP-43 (FTLD-TDP) 变性和肌萎缩侧索硬化症 (ALS)。尽管有共同的病理特征，ALS 和 FTLD-TDP 可能呈现异质的临床特征，包括认知/行为损伤（即 FTLD-TDP）、运动神经元功能障碍（即 ALS）或两者兼而有之（即 ALS-FTD）。此外，某些基因突变通常仅导致 ALS 或 FTLD-TDP，但其他突变可能导致 FLTD-TDP 和/或同一家庭中的 ALS。总之，共同和不同的病理、临床和遗传特征 FTLD-TDP、ALS 和 ALS-FTD 支持以下观点：它们是临床病理学谱的一部分。然而，绝大多数 ALS 和 FTLD-TDP 病例被认为是散发性的，并且没有已知的因果突变。导致观察到的散发性临床异质性的潜在分子机制 TDP-43 蛋白病尚不清楚。支持散发性遗传因素的证据在某些情况下，常见的基因变异与 ALS 或 FTLD-TDP 的疾病风险相关。然而，针对 TDP-43 蛋白病的综合研究很少。因此，风险等位基因的程度这些表型之间的共享或不同尚不清楚。尽管有越来越多的证据表明共享遗传解释导致这两种疾病易感性的生物机制的因素，大大减少努力重点关注 TDP-43 蛋白病的不同遗传特征。识别不同的变体可能有助于我们了解特定疾病的驱动因素。该提案的首要目标是确定驱动个体水平认知/行为和/或的共享和不同的基因组特征这些综合征的神经肌肉表现。观察到 TDP-43 病理学和神经变性与 ALS 和 FTLD-TDP 临床表现相关的特征性神经解剖区域，但是目前还不清楚是什么造成了这种区域选择性脆弱性。之前的工作已经清楚地表明同一个体内基因表达的区域差异。基因表达数量性状位点分析可以识别解释基因表达变异的基因组位点。然而，这些协会高度组织和细胞类型特异性，这可能会掩盖重要的差异。这在内部尤其如此神经退行性疾病，因为观察到的基因表达差异可能反映细胞类型组成差异而不是真正的转录调控。该提案的第二个目标是研究遗传 ALS 中区域特异性差异基因表达（包括细胞类型特异性表达）的贡献和 FTLD-TDP。总体而言，该提案利用基因型和转录组学方法来理解 ALS 和 FTLD-TDP 区域选择性脆弱性的分子贡献。在解开这个异质性，有可能为开发减缓病程的治疗靶点的努力提供信息这些神经退行性疾病。