Rab proteins and alpha-Synuclein toxicity in Neurodegenerative Disease

项目摘要/摘要 本研究的目的是阐明Rab蛋白在突触核蛋白毒性中的作用。阿尔法- 突触核蛋白(？Syn)是帕金森病(PD)和帕金森病(PD)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 Syn的折叠、聚集和沉积被认为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的过度表达干扰了 细胞内转运，导致囊泡异常堆积、聚集和毒性。RAB蛋白是 RAS是小分子GTP结合蛋白的超家族成员，在细胞内具有重要功能 运输，膜运输，甚至神经递质的释放。Rab蛋白在几种细胞中的过表达 帕金森病模型，包括酵母、蠕虫和苍蝇，以及啮齿动物的初级神经元，可以拯救Syn中毒。 此外，在几种神经退行性疾病中，Rab蛋白与Syn的结合增加，包括 DLB，MSA，可能还有PD。突变型Syn的寡聚形式似乎也增加了Rab 有约束力的。我们自己的初步数据证实了Rab蛋白的保护作用，并显示它们也减少了 Syn毒性的细胞模型中存在的Syn寡聚形式的量。总而言之，这些发现支持 假设Syn的积累干扰了正常的Rab功能，通过 中断细胞内的运输。或者，特定的Rab蛋白通常可以预防 有毒Syn物种的形成和积累，但在模型系统中被过度表达所淹没 以及病理性疾病，如帕金森病。因此，增强RAB功能可能提供一种新的治疗方法 帕金森病和相关的神经退行性疾病的机会。因此，拟议的实验将识别 Rab过表达对Syn具有保护作用的机制。 我的长期目标是发展一项旨在理解并最终发现小说的职业 通过基础研究和翻译研究治疗帕金森病和相关的神经退行性疾病。这个 在布拉德利·海曼博士的监督下，拟议的研究和职业发展计划将有所帮助 实现我的眼前目标，获得最新的分子和遗传技能，并学习最先进的技术 影像技术补充了我强大的神经解剖学背景。病毒方面的其他专业知识 Xandra Breakefield博士和Miguel Esteves博士的操纵和CNS基因传递方法也将 提出我最终成为基因治疗专家的目标，并将我的工作转化为潜在的患者 治疗。发展这些研究技能，以及我持续的临床培训和经验是 对于成为一名成功的、独立的临床医生和致力于翻译神经科学的科学家至关重要。

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.