Genetic and environmental modifiers of pathology in amyotrophic lateral sclerosis

创伤性脑损伤(TBI)可能是肌萎缩侧索硬化症(ALS)的危险因素。我们 退伍军人患肌萎缩侧索硬化症的频率增加，退伍军人的头部损伤更高 其流行率高于可比平民人口。重复性头部撞击(RHI)是一种轻微的颅脑损伤， 可导致严重的认知和行为症状以及慢性 创伤性脑病。我们已经证明ALS是CTE中相对常见的一种共病(4)和 这种CTE发生在患有肌萎缩侧索硬化症的退伍军人中。此外，TMEM106B的基因组变异可能起到 在肌萎缩侧索硬化症和CTE疾病进展中发挥重要作用。我们假设TMEM106B是一个修饰语 ALS的疾病表现和严重程度以及创伤性脑损伤和RHI改变TMEM106B与 CTE的病理和临床转归。目前，还没有针对ALS或CTE的疾病修饰疗法， 而且对ALS或CTE疾病表型的遗传修饰因素知之甚少。这很大程度上是因为 到目前为止，还没有系统地收集患有ALS、CTE和两者(ALS+CTE)的参与者。我们的 翻译的方法是系统地解决世界上最大的 经神经病理证实的ALS和CTE受试者的DNA、RNA和蛋白质水平的尸检队列， 目标是确定新的遗传风险因素、生物标记物和机制，这些因素和机制可以作为靶点 药物发现。我们已经证明，与单独的ALS相比，ALS+CTE的共病与 有脑外伤病史，有明显的临床和病理表现。此外，我们还展示了 TMEM106B的这种变异与小胶质细胞激活、tau病理和临床症状有关 CTE。TMEM106B基因的变异也与ALS临床结局的改变有关， 额颞叶变性伴TDP-43包涵体(FTLD-TDP)，并至前颗粒(PRGN)水平和 炎症通路的调节。小胶质细胞激活是ALS和CTE的早期改变，可能 改变疾病进程。我们的假设是，基于我们的初步数据，TMEM106B的变体具有 ALS和ALS的疾病特异性与细胞因子改变、病理和临床疾病进展的相关性 CTE。我们进一步假设TMEM106B的变异与基因表达网络的改变有关 与容易导致ALS、CTE、 ALS+CTE。我们的长期目标是揭示遗传和分子机制 脑损伤背景下ALS和CTE的发展。这个研究项目的直接目标是测试 假设TMEM106B风险等位基因导致炎症基因表达改变，并确定 TMEM106B相关疾病修饰基因网络和神经炎性标志物 生物标记物，以识别那些有患ALS和CTE风险的人，并揭示 可能成为治疗的靶点。总体而言，我们的目标是将脑外伤的历史与遗传、基因表达和蛋白质联系起来 确诊为ALS、CTE和ALS+CTE的人类受试者中的变异。

Traumatic brain injury (TBI) may be a risk factor for the development of amyotrophic lateral sclerosis (ALS). US military veterans have an increased frequency of ALS, and the veteran population has higher head injury prevalence than the comparable civilian population. Repetitive head impacts (RHI) are a form of mild TBI that can lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic traumatic encephalopathy (CTE). We have shown that ALS is a relatively frequent comorbidity in CTE (4) and that CTE occurs in a veteran population with ALS. Furthermore, genomic variation in TMEM106B may play an important role in both ALS and CTE disease progression. We hypothesize that TMEM106B is a modifier of disease presentation and severity in ALS and that TBI and RHI alter the associations of TMEM106B with pathology and clinical outcomes in CTE. Currently, there are no disease modifying treatments for ALS or CTE, and little is known about genetic modifiers of disease phenotype in ALS or CTE. This is largely because there has not been a systematic collection of participants with ALS, CTE, and both (ALS+CTE) until now. Our translational approach is to systematically address neurodegeneration in the world’s largest neuropathologically-confirmed autopsy cohort of ALS and CTE subjects on the DNA, RNA, and protein levels, with the goal of identifying novel genetic risk factors, biomarkers, and mechanisms that can be targeted for drug discovery. We have shown that compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation. Furthermore, we have demonstrated that variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in CTE. Variation in TMEM106B is also related to altered clinical outcomes in ALS, the development of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), and to progranulin (PRGN) levels and modulation of inflammatory pathways. Microglial activation is an early change in both ALS and CTE and may alter disease progression. Our hypothesis, based on our preliminary data, is that variants of TMEM106B have disease-specific associations with altered cytokines, pathology, and clinical disease progression in ALS and CTE. We further hypothesize that TMEM106B variation is associated with altered gene expression networks related to inflammatory pathways that predispose to worse pathological and clinical outcomes in ALS, CTE, and ALS+CTE. Our long-term goal is to uncover genetic and molecular mechanisms underlying the development of ALS and CTE in the setting of TBI. The immediate goal of this research project is to test the hypothesis that the TMEM106B risk allele leads to altered inflammatory gene expression and to determine TMEM106B-related disease modifying gene networks and neuroinflammatory markers that may serve as biomarkers to identify those individuals at risk for developing ALS and CTE and to uncover mechanisms that may be targeted for therapy. Overall, we aim to link a history of TBI to genetic, gene expression, and protein variation in human subjects with a definitive pathological diagnosis of ALS, CTE, and ALS+CTE.