Ataxin-2 as a genetic risk factor for ALS: New insights into neurodegeneration

Ataxin-2 作为 ALS 的遗传危险因素：对神经退行性变的新见解

• 批准号: 8471799
• 负责人: Nancy M Bonini
• 金额: $ 33万
• 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: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471799
• 关键词: 22q; Address; Adult; Affect; Amyotrophic Lateral Sclerosis; Cause of Death; Cell Culture Techniques; Cells; Data; Disease; Disease model; Disease susceptibility; Dose; Drosophila genus; Employee Strikes; Family; Foundations; Frontotemporal Lobar Degenerations; Gene Targeting; Genes; Genetic; Genetic Screening; Goals; Human; Individual; Lead; Length; Mammalian Cell; Metabolism; Motor Neurons; Muscle; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Onset of illness; Paralysed; Parkinson Disease; Pathology; Pathway interactions; Patients; Predisposition; Process; Proteins; RNA; RNA-Binding Proteins; Research Proposals; Risk Factors; Role; SCA2 protein; Spinal Cord; System; Tertiary Protein Structure; Testing; Therapeutic; Toxic effect; Type 2 Spinocerebellar Ataxia; Yeasts; age related; fly; genetic risk factor; insight; novel therapeutic intervention; novel therapeutics; polyglutamine; protein TDP-43; therapeutic target

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that wreaks havoc on motor neurons. Recently, a central role for RNA binding proteins and RNA metabolism pathways has emerged. TDP-43 is an RNA binding protein that has been identified as a component of pathological inclusions in neurons of most ALS patients. Further, pathogenic mutations in the gene encoding TDP-43 (TARDBP) are associated with familial and sporadic ALS cases. These data argue that pathological activities of TDP-43 are critical to ALS. Despite the central importance of TDP-43, however, little is understood about how it causes disease and protein interaction partners that lead to ALS. This Co-PI research proposal brings together two experts in yeast and fly genetics who have made fundamental discoveries into mechanisms of devastating human age-related diseases such as Parkinson's disease and ALS using these simple but powerful systems. Importantly, discoveries made in yeast are translatable to Drosophila disease models, and from yeast and flies to human patients. Using these systems, we have found that ataxin-2, a polyglutamine (polyQ) protein, whose polyQ repeat expansions cause spinocerebellar ataxia type 2 (SCA2), is a potent modifier of TDP-43 toxicity in yeast and fly. Launching from this finding, we tested and found that polyQ expansions of 27-33Qs in the human ataxin-2 gene, ATXN2, are significantly associated with ALS. These data argue that ATXN2 is a new and relatively common ALS susceptibility disease gene, and that the TDP-43/Atx2 interaction is a critical target in ALS and perhaps other diseases associated with TDP-43 pathology. With the goal to reveal mechanistic insight into this interaction, we propose three Specific Aims. In Aim 1, we will use mammalian cell culture and Drosophila to define the domains of the TDP-43 and ataxin-2 proteins that are critical for the synergistic interaction in degeneration and function. These studies will provide insight into the activity of the proteins and processes affected in the pathological situation. In Aim 2, we will use the power of fly genetics to define additional genes critical for the synergy between TDP-43 and ataxin-2. This will reveal understanding of the processes perturbed and new pathways for therapeutic targeting. Finally, in Aim 3, we will address the greater role of ataxin-2 in neurodegeneration. ALS shares a disease spectrum with frontotemporal lobar degeneration (FTLD) and TDP- 43 pathology characterizes other neurodegenerative diseases. We will assess polyQ repeat lengths of ataxin-2 in other diseases to assess whether expansions occur in related disorders. Taken together, these findings will reveal key aspects of the TDP-43/ataxin-2 interaction central to ALS, the broader role of ataxin-2 in neurodegenerative disease, and the foundation for novel therapeutic insights.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种破坏性神经退行性疾病，会对运动神经元造成严重破坏。最近，RNA 结合蛋白和 RNA 代谢途径的核心作用已经显现。 TDP-43 是一种 RNA 结合蛋白，已被鉴定为大多数 ALS 患者神经元病理包涵体的组成部分。此外，编码 TDP-43 (TARDBP) 的基因的致病性突变与家族性和散发性 ALS 病例相关。这些数据表明 TDP-43 的病理活动对于 ALS 至关重要。然而，尽管 TDP-43 至关重要，但人们对它如何导致疾病以及导致 ALS 的蛋白质相互作用伙伴知之甚少。 这项 Co-PI 研究计划汇集了两位酵母和果蝇遗传学专家，他们利用这些简单但功能强大的系统，对破坏人类年龄相关疾病（如帕金森病和肌萎缩侧索硬化症）的机制做出了基础性发现。重要的是，在酵母中取得的发现可以转化为果蝇疾病模型，并从酵母和果蝇转化为人类患者。使用这些系统，我们发现 ataxin-2（一种聚谷氨酰胺 (polyQ) 蛋白）是酵母和果蝇中 TDP-43 毒性的有效调节剂，其 PolyQ 重复扩增会导致 2 型脊髓小脑共济失调 (SCA2)。基于这一发现，我们进行了测试，发现人类 ataxin-2 基因 ATXN2 中 27-33Q 的 PolyQ 扩展与 ALS 显着相关。这些数据表明，ATXN2 是一种新的且相对常见的 ALS 易感疾病基因，并且 TDP-43/Atx2 相互作用是 ALS 以及可能与 TDP-43 病理学相关的其他疾病的关键靶标。为了揭示这种相互作用的机制洞察，我们提出了三个具体目标。在目标 1 中，我们将使用哺乳动物细胞培养物和果蝇来定义 TDP-43 和 ataxin-2 蛋白的结构域，这些结构域对于变性和功能的协同相互作用至关重要。这些研究将深入了解病理情况下受影响的蛋白质的活性和过程。在目标 2 中，我们将利用果蝇遗传学的力量来定义对 TDP-43 和 ataxin-2 之间的协同作用至关重要的其他基因。这将揭示对扰动过程的理解以及治疗靶向的新途径。最后，在目标 3 中，我们将讨论 ataxin-2 在神经退行性变中的更大作用。 ALS 与额颞叶变性 (FTLD) 具有相同的疾病谱，而 TDP-43 病理学是其他神经退行性疾病的特征。我们将评估其他疾病中ataxin-2的polyQ重复长度，以评估相关疾病中是否发生扩增。总而言之，这些发现将揭示 TDP-43/ataxin-2 相互作用对 ALS 至关重要的关键方面、ataxin-2 在神经退行性疾病中的更广泛作用，以及新的治疗见解的基础。