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

定义 Ataxin-2 在 ALS 和 TDP-43 蛋白病中的作用

• 批准号: 8332945
• 负责人: Michael P Hart
• 金额: $ 1.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-05 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332945
• 关键词: Address; Affect; Amyotrophic Lateral Sclerosis; Autopsy; Biochemical; Brain; CAG repeat; Cells; Cessation of life; Classification; Cytoplasm; DNA; Disease; Disease model; Familial Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Genes; Genomics; Glutamine; Goals; Hand; Heterogeneity; Human; Human Cell Line; Human Genetics; Investigation; Knowledge; Learning; Length; Link; Methods; Modeling; Molecular; Motor Neurons; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear Protein; Pathogenesis; Pathologic; Pathology; Pathology processes; Pathway interactions; Patients; Phosphorylation; Predisposition; Process; Proteins; RNA; Research; Risk; Role; SCA2 protein; Specificity; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Type 2 Spinocerebellar Ataxia; Ubiquitination; Variant; Yeasts; base; fly; genetic risk factor; human tissue; insight; neuropathology; novel; patient population; polyglutamine; protein TDP-43; research study; stem; therapeutic target

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.

描述（由申请人提供）：神经退行性疾病目前几乎没有治疗方法，也没有治愈方法。这源于对神经变性中神经元死亡的原因缺乏了解。最近的研究重点是发现在患者大脑中积累的蛋白质，包括肌萎缩侧索硬化症（ALS）中的TDP-43，已经开始研究了解疾病的机制。使用致病性疾病蛋白质建模疾病已被证明可用于识别参与神经变性的潜在途径、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，我们已经确定了TDP-43和Ataxin-2之间的新型相互作用，Ataxin-2是另一种神经退行性疾病脊髓小脑共济失调2型（SCA 2）中突变的蛋白质。我们将Ataxin-2的突变确定为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相互作用作为一种潜在的致病机制，不仅可以提供疾病过程的知识，还可以作为一种潜在的治疗靶点。因此，我将首先定义蛋白质相互作用所需的Ataxin-2和TDP-43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。这将涉及神经病理学和用于分析人体组织的生物化学方法的培训。最后，我将研究Ataxin-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。建议的这一方面将需要在人类遗传学方法和分析以及组织病理学技术方面进行培训。我们发现Ataxin- 2通过与TDP-43的相互作用在ALS中发挥作用，这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相互作用的了解，更广泛地说，将深入了解不同相关神经退行性疾病机制的相似性和差异性。