Shared and disparate genomic features of TDP-43 proteinopathies

项目摘要/摘要 TAR DNA结合~43 kDa(TDP-43)包涵体是额颞叶的病理标志 TDP-43变性(FTLD-TDP)和肌萎缩侧索硬化症(ALS)。尽管有共同的病态 ALS和FTLD-TDP可呈现不同的临床特征，包括认知/行为 损害(即FTLD-TDP)、运动神经元功能障碍(即ALS)或两者兼而有之(即ALS-FTD)。而且，一定 基因突变通常只会导致ALS或FTLD-TDP，但其他突变可能会导致FLTD-TDP和/或 同一家庭中的肌萎缩侧索硬化症。共同的和不同的病理、临床和遗传特征 FTLD-TDP、ALS和ALS-FTD支持它们是临床病理谱的一部分的概念。然而， 绝大多数ALS和FTLD-TDP病例被认为是散发性的，没有已知的原因突变。 引起散发性疾病临床异质性的潜在分子机制 TDP-43蛋白病变还不是很清楚。支持零星遗传成分的证据 在病例中，常见的基因变异与ALS或FTLD-TDP的疾病风险有关。 然而，跨TDP-43蛋白病变的联合研究很少见。因此，风险等位基因的程度 这些表型的共同或不同尚不清楚。虽然有越来越多的证据表明 解释导致这两种疾病易感性的生物机制的因素，要少得多 专注于TDP-43蛋白病中不同的遗传特征。识别不同的变体 可能有助于我们理解特定疾病的驱动因素。这项提案的第一个目标是确定两者 共同和不同的基因组特征驱动个人水平的认知/行为和/或 这些综合征的神经肌肉表现。TDP-43的病理和神经变性观察 与ALS和FTLD-TDP临床表现相关的特征性神经解剖学区域，但 目前还不清楚是什么导致了这种地区性的选择性脆弱性。以前的工作已经证明了 同一个体内基因表达的地区差异。基因表达数量性状基因座 分析可以确定解释基因表达差异的基因组位置。然而，这些关联是 高度的组织和细胞类型特异性，这可能会掩盖重要的差异。这一点在内部尤其如此 神经退行性疾病，因为观察到的基因表达差异可能反映了细胞类型的组成 差异，而不是真正的转录调控。这项提议的第二个目标是研究基因 在ALS中对区域特异性差异基因表达的贡献，包括细胞类型特异性表达 和FTLD-TDP。总体而言，这一建议利用了基因分型和转录切分的方法来理解 ALS和FTLD-TDP中区域选择性脆弱性的分子贡献。在解决这一问题上 异质性，这可能是可能的努力，开发治疗靶点，以减轻病程 这些神经退行性疾病。

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.