Shared and disparate genomic features of TDP-43 proteinopathies

项目概要/摘要 TAR DNA结合~ 43 kDa（TDP-43）包涵体是额颞叶肿瘤的病理标志 与TDP-43（FTLD-TDP）和肌萎缩侧索硬化（ALS）的变性。尽管有共同的病理 ALS和FTLD-TDP可表现出异质性临床特征，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（即，ALS-FTD）。此外，某些 基因突变通常仅导致ALS或FTLD-TDP，但其他突变可导致FLTD-TDP和/或 在同一个家庭里。总之，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学谱的一部分的观点。然而，在这方面， 绝大多数ALS和FTLD-TDP病例被认为是散发的，并且没有已知的致病突变。 导致在散发性肿瘤中观察到的临床异质性的潜在分子机制 TDP-43蛋白质病尚未完全了解。支持遗传成分的证据 在一些病例中，常见的遗传变异与ALS或FTLD-TDP的疾病风险相关。 然而，TDP-43蛋白病的联合研究很少。因此，风险等位基因在多大程度上 在这些表型中共有的或不同的尚不清楚。虽然有越来越多的证据表明， 这些因素解释了驱动对这两种疾病易感性的生物机制， 专注于TDP-43蛋白质病的不同遗传特征。识别不同的变体 可能有助于我们理解疾病特异性驱动因素。本建议的第一个目的是确定 共同的和不同的基因组特征，驱动个体水平的认知/行为和/或 这些综合征的神经肌肉表现。TDP-43病理学和神经退行性变在小鼠中观察到。 与ALS和FTLD-TDP的临床表现相关的特征性神经解剖区域，但 造成这种区域性选择性脆弱性的原因尚不清楚。以往的研究表明， 同一个体内基因表达的区域差异。基因表达数量性状位点 分析可以鉴定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，这可能掩盖重要差异。尤其是在 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组成 差异，而不是真正的转录调控。这项建议的第二个目的是研究遗传学。 ALS中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。总的来说，这项提案利用基因型和转录组学方法来了解 ALS和FTLD-TDP的区域选择性脆弱性的分子贡献。在解开这个 异质性，这可能是有可能的通知努力开发治疗靶点，减弱的过程中， 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.