Defining the role of Ataxin-2 in ALS and TDP-43 proteinopathies

描述（申请人提供）：神经退行性疾病目前治疗方法很少，无法治愈。这源于缺乏对神经退行性疾病中神经元死亡原因的理解。最近的研究重点是发现在患者大脑中积累的蛋白质，包括肌萎缩性侧索硬化症（ALS）中的TDP-43，这使得研究朝着了解疾病背后的机制方向发展。利用病原性疾病蛋白建立疾病模型已被证明有助于识别神经退行性疾病的潜在途径、相互作用和机制。在这个提案中，我将研究TDP-43，一种与ALS和额颞叶痴呆有关的病理蛋白，这两种疾病都是毁灭性的神经退行性疾病。通过在酵母和苍蝇中模拟TDP-43相关疾病，我们发现了TDP-43和Ataxin-2之间的一种新的相互作用，Ataxin-2是另一种神经退行性疾病脊髓小脑性共济失调2型（SCA2）中突变的蛋白质。我们发现Ataxin-2突变是ALS的一种新的遗传风险因素，可能是迄今为止发现的最常见的。TDP-43/Ataxin-2相互作用被认为是一种潜在的致病机制，不仅可以提供疾病过程的知识，还可以作为潜在的治疗靶点。因此，我将首先定义Ataxin-2和TDP-43蛋白相互作用所需的结构域。其次，我将确定Ataxin-2的突变是否影响TDP-43的病理特征，包括蛋白质的下游生化改变，以了解这些突变是否影响已知的疾病过程。这将包括神经病理学和用于分析人体组织的生化方法的培训。最后，我将研究Ataxin-2的突变是否会导致与ALS相关的其他神经退行性疾病，这些疾病也显示TDP-43的参与。这方面的建议将需要训练人类遗传学方法和分析，以及组织病理学技术。我们通过与TDP-43的相互作用发现Ataxin- 2在ALS中的作用，为研究开辟了许多新的途径。这些实验将扩大我们对TDP-43/Ataxin-2相互作用的认识，并更广泛地深入了解不同相关神经退行性疾病机制的异同。

DESCRIPTION (provided by applicant): Neurodegenerative diseases currently have few treatments and no cures. This stems from the lack of understanding of the causes of neuron death in neurodegeneration. Recent research focusing on the proteins discovered to accumulate in the brains of patients, including TDP-43 in amyotrophic lateral sclerosis (ALS), has taken research towards understanding the mechanisms that underlie disease. Modeling disease using pathogenic disease proteins has proved useful for identifying potential pathways, interactions and mechanisms involved in neurodegeneration. In this proposal I will study TDP-43, a pathological protein involved in ALS and frontotemporal dementia, both devastating neurodegenerative disorders. Through modeling TDP-43 related disease in yeast and flies, we have identified a novel interaction between TDP-43 and Ataxin-2, a protein mutated in another neurodegenerative disease, spinocerebellar ataxia type 2 (SCA2). We identified mutations in Ataxin-2 as a novel genetic risk factor for ALS, potentially the most common discovered to date. The TDP-43/Ataxin-2 interaction sits poised as a potential pathogenic mechanism that could provide not only knowledge of disease processes, but also as a potential therapeutic target. Therefore, I will first define the domains of Ataxin-2 and TDP-43 required for the proteins to interact with each other. Second, I will determine if mutations in Ataxin-2 affect the pathological signature of TDP-43, which includes downstream biochemical alterations of the protein, to learn if these mutations influence known disease processes. This will involve training in neuropathology and biochemical methods used to analyze human tissue. Lastly, I will examine if mutations in Ataxin-2 contribute to other neurodegenerative diseases related to ALS that also show TDP-43 involvement. This aspect of the proposal will require training in human genetics methods and analyses, as well as histopathological techniques. Our discovery of a role for Ataxin- 2 in ALS via an interaction with TDP-43 opens up many new avenues for investigation. These experiments will expand our knowledge of the TDP-43/Ataxin-2 interaction and, more broadly, give insight into the similarities and differences of mechanisms underlying different related neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: My proposed experiments and results will aid in the understanding of how a new genetic risk factor contributes to disease, as well as address potential mechanisms underlying a common pathogenic protein. This will give a greater understanding of neurodegenerative disease processes and provide knowledge about a potential therapeutic target for ALS, and perhaps other related neurodegenerative diseases.