Rab proteins and alpha-Synuclein toxicity in Neurodegenerative Disease

项目总结/摘要 拟议研究的目的是阐明Rab蛋白在突触核蛋白毒性中的作用。阿尔法- 突触核蛋白（Synn）是在帕金森病（PD）中病理发现的路易体的主要成分， 相关疾病，如路易体痴呆（DLB）和多系统萎缩（MSA）。异常 据信，Syn的折叠、聚集和沉积是神经元发育的中心。 功能障碍和退化。 最近在酵母中的数据表明，Syn的过表达干扰了 细胞内运输并导致异常囊泡积聚、聚集和毒性。Rab蛋白是 小GTP结合蛋白Ras超家族成员，在细胞内 运输，膜运输，甚至神经递质释放。Rab蛋白在几种细胞中的过表达 PD模型，包括酵母，蠕虫和苍蝇，以及啮齿动物初级神经元，拯救了Syn毒性。 此外，Rab蛋白在几种神经退行性疾病中与Syn的结合增加，包括 DLB，MSA，可能还有PD。寡聚体形式的突变体<$Syn似乎也增加了Rab， 约束力我们自己的初步数据证实了Rab蛋白的保护作用，并表明它们也减少了 Syn毒性细胞模型中存在的Syn寡聚体形式的量。总之，这些发现支持了 假设Syn的积累干扰了正常的Rab功能，导致毒性， 破坏细胞内运输。 或者，特定的Rab蛋白通常可以保护免受 有毒的Syn种类的形成和积累，但在模型系统中被过度表达所淹没 和病理状况，如PD。 因此，增强Rab功能可能提供一种新的治疗方法， PD和相关神经退行性疾病的机会。因此，拟议的实验将辨别 Rab过表达赋予对抗Syn的保护机制。 我的长期目标是发展一个旨在理解并最终发现小说的职业生涯。 通过基础和转化研究，为PD和相关神经退行性疾病提供治疗。 的 在布拉德利·海曼博士的监督下，我提出了一项研究和职业发展计划，这将有助于 实现我的近期目标，以获得最新的分子和遗传技能，并学习最先进的 成像技术来补充我强大的神经解剖学背景。 病毒方面的其他专业知识 Xandra Breakefield和Miguel Esteves博士的操作和CNS基因递送方法也将 我的目标是最终成为一名基因治疗专家，并将我的工作转化为潜在的患者。 治疗 发展这些研究技能，沿着我持续的临床培训和经验， 成为一个成功的，独立的临床科学家致力于转化神经科学的关键。

Project Summary/Abstract The objective of the proposed research is to elucidate the role of Rab proteins in ¿-synuclein toxicity. Alpha- synuclein (¿Syn) is a principal component of Lewy bodies found pathologically in Parkinson disease (PD) and related disorders, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Abnormal folding, aggregation, and deposition of ¿Syn are believed to be central to development of neuronal dysfunction and degeneration. Recent data in yeast indicate that overexpression of ¿Syn interferes with intracellular trafficking and results in abnormal vesicle accumulation, clustering, and toxicity. Rab proteins are members of the Ras super-family of small GTP-binding proteins and have critical functions in intracellular trafficking, membrane transport, and even neurotransmitter release. Overexpression of Rab proteins in several PD models, including yeast, worms, and flies, as well as rodent primary neurons, rescues ¿Syn toxicity. Moreover, Rab proteins show increased binding to ¿Syn in several neurodegenerative disorders, including DLB, MSA, and possibly also PD. Oligomeric forms of mutant ¿Syn likewise appear to have increased Rab binding. Our own preliminary data confirm Rab proteins' protective role, and show that they also reduce the amount of oligomeric forms of ¿Syn present in cell models of ¿Syn toxicity. Together, these findings support the hypothesis that accumulation of ¿Syn interferes with normal Rab function, leading to toxicity via disruption of intracellular trafficking. Alternatively, specific Rab proteins may normally protect against formation and accumulation of toxic ¿Syn species, but are overwhelmed by overexpression in model systems and pathological conditions, such as PD. Enhancing Rab function may thus provide a new therapeutic opportunity for PD and related neurodegenerative disorders. The proposed experiments will therefore discern the mechanisms whereby Rab overexpression confers protection against ¿Syn. My long-term goal is to develop a career aimed at understanding and ultimately finding novel therapies for PD and related neurodegenerative disorders through basic and translational research. The proposed research and career development plan, under the supervision of Dr. Bradley Hyman, will help achieve my immediate goals to obtain up-to-date molecular and genetic skills and to learn state-of-the-art imaging techniques to complement my strong neuroanatomical background. Additional expertise in viral manipulation and CNS gene delivery methods from Drs. Xandra Breakefield and Miguel Esteves will also forward my goal of eventually becoming a gene therapy expert and translating my work into potential patient therapies. Developing these research skills, along with my continued clinical training and experience are critical to becoming a successful, independent clinician-scientist committed to translational neuroscience.