Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS

细胞内RNA结合蛋白TDP43的错误定位和神经元的过度兴奋性是主要的 TDP43相关性额颞叶痴呆(FTD)和肌萎缩侧索硬化症(ALS)的特点核子 超过一半的FTD患者存在TDP43的排斥和胞浆沉积，近95%的FTD患者 对于肌萎缩侧索硬化症，但这些变化的起源仍不清楚。同样，神经元的过度兴奋性也是一种 在FTD/ALS患者中普遍发现，体内和体外疾病模型，但原因和后果 这一现象尚不清楚。我们的初步数据首次显示出 TDP43沉积和神经元超兴奋性可能在神经退行性变中起关键作用 在TDP43相关的FTD/ALS中观察到。神经元活性升高上调一种罕见的TDP43亚型 它缺乏蛋白质中典型的、低复杂性的羧基末端。由于它活跃的核出口和它的 结合全长(FL)TDP43的能力，这种缩短的(S)TDP43亚型从细胞核中活跃地输出， 在胞质聚集体中积累，并隔离全长(F1)TDP43，从而重现TDP43 FTD/ALS的病理学。我们这个项目的中心目标是确定sTDP43在FTD/ALS中的影响 发病机制，长期目标是确定针对TDP43的新的有效治疗策略 动态平衡。我们将通过以下方式测试sTDP43导致TDP43相关FTD/ALS神经退行性变的假设 三个具体目标。首先，我们将利用我们开发的sTDP43特异性抗体 确定sTDP43在大量散发性和家族性人群中积聚的患病率和分布 由密歇根大学脑库策划的FTD/ALS病例。我们还将调查 STDP43对RNA动态平衡的影响，以及sTDP43与应激、应激颗粒的关系。 疾病模型。最后，我们将评估sTDP43在啮齿动物初级神经变性中的作用。 FTD/ALS相关患者的神经元和人诱导的多能干细胞来源的神经元 C9ORF72六核苷酸扩增突变。在这些研究完成后，我们将会勾勒出 TDP43相关的FTD/ALS中导致神经退行性变的独特疾病机制，并突出了潜在的 治疗方法侧重于毒性TDP43亚型的异常活性依赖产生。

Cytosolic mislocalization of the RNA binding protein TDP43 and neuronal hyperexcitability are cardinal features of TDP43-related frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Nuclear exclusion and cytosolic deposition of TDP43 are found in over half of those with FTD, and nearly 95% of those with ALS, but the origin of these changes remains unknown. Likewise, neuronal hyperexcitability is a ubiquitous finding in FTD/ALS patients, in vivo and in vitro disease models, yet the cause and consequences of this phenomenon are unclear. Our preliminary data show for the first time an intrinsic connection between TDP43 deposition and neuronal hyperexcitabilty that may play a pivotal part in the neurodegeneration observed in TDP43-related FTD/ALS. Elevated neuronal activity upregulates an uncommon TDP43 isoform that lacks the canonical, low-complexity carboxy-terminus of the protein. Due to its active nuclear export and its ability to bind full-length (fl)TDP43, This shortened (s)TDP43 isoform is actively exported from the nucleus, accumulates in cytosolic aggregates, and sequestrates full-length (fl)TDP43, thereby recapitulating TDP43 pathology in FTD/ALS. Our central goal with this project is to determine the impact of sTDP43 in FTD/ALS pathogenesis, with a long-term objective of defining novel and effective therapeutic strategies targeting TDP43 homeostasis. We will test the hypothesis that sTDP43 drives neurodegeneration in TDP43-related FTD/ALS by three specific aims. First, we will take advantage of an sTDP43-specific antibody that we developed to determine the prevalence and distribution of sTDP43 accumulation in a large cohort of sporadic and familial FTD/ALS cases curated by the University of Michigan Brain Bank. We will also investigate the impact of sTDP43 on RNA homeostasis, and determine the relationship between sTDP43, stress, and stress granules in disease models. Lastly, we will assess the contribution of sTDP43 to neurodegeneration in rodent primary neurons and human induced pluripotent stem cell-derived neurons from patients carrying FTD/ALS-associated C9orf72 hexanucleotide expansion mutations. At the completion of these studies, we will have delineated a unique disease mechanism leading to neurodegeneration in TDP43-related FTD/ALS, and highlighted potential therapeutic approaches focusing on the abnormal activity-dependent production of toxic TDP43 isoforms.