Ataxin-2 complex proteins in neurodegeneration.

项目摘要/摘要 此R35提案建立在由Javits R37和U01 Create Bio奖以及 主要研究人员小组从机械发现中领导的长期成功 脊髓小脑性共济失调和转化为新的治疗方法，其中一项目前正处于1期人体试验 (BIIB105)。该提案的统一主题是关注ATXN2-Of复合体中的RNA结合蛋白(RBPs) 指导RNA代谢的几个方面的蛋白质，这些蛋白质容易出现相分离和 聚合。以我们在聚谷氨酰胺介导的神经变性和神经元方面的最新发现为基础 Staufen-1(STAU1)过多，我们将应用多维方法来定义新的致病 它们与自噬、未折叠蛋白反应(UPR)和RNA相交的机制 新陈代谢和运输。我们假设，这些反应虽然在短期内是补偿性的，但会成为 与持续的压力不适应，RBP网络反应导致进行性恶化 自噬通量和凋亡信号的放大。我们已经建立了一套广泛的创新工具 和独特的模型，在一个特殊的研究环境中，与当地和国家的成熟合作伙伴合作 我们多年来一直与他们共享资源。我们的方法一直是描述小脑的特征 在多个时间点使用全基因组转录、蛋白质组、形态、生理的退化 和行为技术。这些基础将使我们能够迅速从细胞模型发展到动物模型 体外和体内特定基因的修饰剂量。我们现在将这种方法从Purkinje细胞扩展到 脊髓运动神经元使我们能够解决与遗传性和散发性广泛相关的基本问题 神经退行性疾病。这些热点问题包括：细胞质限制性商业惯例的作用，特别是ATXN_2 和STAU1，对营养、化学和突变蛋白胁迫的响应；它们的调控和相互作用 相互作用，以及决定自噬通量和UPR的关键蛋白质；它们对神经元死亡的整体影响； 最后，它们有望成为使用小分子和RNA导向疗法的治疗靶点。R35 资金将使我们能够确定ATXN2-复合体中蛋白质在神经退行性变和 定义不同神经退行性疾病的共同特征，不仅与 遗传性，但也可导致散发性共济失调和运动神经元病。我们提议的广泛范围 研究将使具有不同背景的科学家参与实验室和部门文化 包容性和多样性。凭借我们对动物模型和基因重复性的既定承诺 以目标为目标的方法，小说的机械性见解为翻译成发展中的小说带来了希望 神经退行性疾病的治疗。

Project Summary/Abstract This R35 proposal builds on experiments supported by a Javits R37 and a U01 CREATE Bio award and the longstanding success of the principal investigator’s group leading from mechanistic discoveries in spinocerebellar ataxias and translation to novel treatments, one of which is now in a phase 1 human trial (BIIB105). The proposal’s unifying theme is a focus on RNA-binding proteins (RBPs) in the ATXN2-complex of proteins that direct several aspects of RNA metabolism and that are prone to phase-separation and aggregation. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and neuronal staufen-1 (STAU1) overabundance, we will apply multi-dimensional approaches to define novel pathogenic mechanisms in their intersections with autophagy, the unfolded protein response (UPR), and with RNA metabolism and transport. We postulate that these responses, while compensatory in the short term, become maladaptive with sustained stress and that an RBP network response leads to progressive deterioration of autophagic flux and amplification of apoptotic signaling. We have established a broad suite of innovative tools and unique models in an exceptional research environment with established local and national collaborators with whom we have shared resources over many years. Our approach has been to characterize cerebellar degeneration at multiple time points using genome-wide transcriptomic, proteomic, morphologic, physiologic and behavioral techniques. These foundations will allow us to rapidly progress from cellular to animal models modifying dosage of specific genes in vitro and in vivo. We will now extend this approach from Purkinje cells to spinal motor neurons enabling us to address fundamental issues of broad relevance to inherited and sporadic neurodegenerative diseases. These topical issues include: the role of cytoplasmic RBPs, especially ATXN2 and STAU1, in response to nutrient, chemical and mutant protein stress; their regulation and interplay with each other, and key proteins determining autophagic flux and the UPR; their overall effect on neuronal death; and finally, their promise as therapeutic targets using small molecules and RNA-directed therapies. R35 funding will allow us to identify novel functions of proteins in the ATXN2-complex in neurodegeneration and define shared features across different neurodegenerative diseases with particular relevance not only to inherited, but also to sporadic forms of ataxia and motor neuron disease. The broad scope of our proposed studies will enable participation of scientists with diverse backgrounds in a laboratory and departmental culture of inclusivity and diversity. With our established commitment to reproducibility of animal models and gene targeting approaches, the novel mechanistic insights hold promise for translation into developing novel treatments for neurodegenerative disorders.