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很少，也没有治愈方法。这源于对神经退行性变中神经元死亡的原因缺乏了解。最近对发现在患者大脑中积聚的蛋白质的研究，包括肌萎缩侧索硬化症(ALS)中的TDP-43，已经开始研究以了解疾病的基础机制。使用致病蛋白对疾病进行建模已被证明有助于确定神经退行性变的潜在途径、相互作用和机制。在这项提案中，我将研究TDP-43，这是一种与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。通过在酵母和果蝇中模拟TDP-43相关疾病，我们发现了TDP-43和Aaxin-2之间的一种新的相互作用，Aaxin-2是另一种神经退行性疾病脊髓小脑型共济失调2(SCA2)中突变的蛋白质。我们确定Aaxin-2突变是ALS的一种新的遗传风险因素，这可能是迄今为止发现的最常见的因素。TDP-43/Aaxin-2的相互作用可能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，我将首先定义蛋白质相互作用所需的Aaxin-2和TDP-43结构域。其次，我将确定Aaxin-2的突变是否会影响TDP-43的病理特征，其中包括蛋白质的下游生化变化，以了解这些突变是否会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Aaxin-2的突变是否有助于与ALS相关的其他神经退行性疾病，这些疾病也显示TDP-43参与。该提案的这一方面将需要对人类遗传学方法和分析以及组织病理学技术进行培训。我们通过与TDP-43的相互作用发现了Aaxin-2在肌萎缩侧索硬化症中的作用，为研究开辟了许多新的途径。这些实验将扩大我们对TDP-43/Aaxin-2相互作用的了解，并从更广泛的角度，深入了解不同相关神经退行性疾病发病机制的异同。 公共卫生相关性：我提出的实验和结果将有助于理解一种新的遗传风险因素如何导致疾病，以及解决常见致病蛋白潜在的机制。这将使我们更好地了解神经退行性疾病的过程，并为ALS，也许还有其他相关的神经退行性疾病提供潜在的治疗靶点。

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.