Extracellular alpha-synuclein in Parkinson's Disease

帕金森病中的细胞外 α-突触核蛋白

• 批准号: 8234547
• 负责人: Pamela J McLean
• 金额: $ 14.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234547
• 关键词: Affect; Alpha-Synuclein transgenic mouse; Animal Model; Autophagocytosis; Biological; Biological Assay; Biology; Cell Survival; Cells; Cephalic; Cerebrospinal Fluid; Clinic; Clinical; Conditioned Culture Media; Data; Development; Devices; Disease; Disease Progression; Endocytic Vesicle; Extracellular Space; Goals; Human; In Vitro; Kinetics; Laboratories; Lead; Lewy Bodies; Life; Microdialysis; Microfluidics; Microscopic; Modeling; Molecular; Molecular Sieve Chromatography; Mus; Nerve Degeneration; Neurons; Parkinson Disease; Pathway interactions; Patients; Preparation; Proteins; Publishing; Rattus; Role; Series; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Topical application; Toxic effect; Transgenic Mice; Translations; Transplantation; alpha synuclein; cellular imaging; extracellular; genetic manipulation; in vivo; inhibition of autophagy; innovation; mouse model; neurotoxic; novel; novel therapeutics; protein misfolding; research study; tool; transmission process; uptake

DESCRIPTION (provided by applicant): The goal of this application is to investigate the impact of extracellular alpha-synuclein on neurodegeneration and disease progression in Parkinson's disease (PD). There are several reasons to target extracellular alpha-synuclein for the development of novel therapeutic agents for PD including the fact that Lewy bodies containing alpha-synuclein have been found in healthy grafted neurons in PD patients several years after transplant suggesting a possible role for alpha-synuclein transmission in disease propagation and progression. We have proposed complementary approaches to elucidate not only the fundamental mechanisms and species involved in alpha-synuclein release, but to develop unique therapeutic interventions that target extracellular alpha- synuclein oligomers with a view that understanding extracellular alpha-synuclein biology can lead to a translation of new or different therapeutic approaches. We will examine 3 major aims: The first aim will define the types of alpha-synuclein released from neurons using a series of biophysical and molecular tools that allow characterization of released oligomeric forms of alpha-synuclein. We will also investigate the mechanisms involved in the release and uptake of alpha-synuclein and the impact of extracellular alpha-synuclein on cell viability .The second aim will expand on our preliminary studies and on recently published studies to investigate pathways involved in alpha-synuclein release and uptake and in particular the role of macroautophagy in alpha-synuclein release and uptake. Finally, the third aim extends these observations in vivo, utilizing in vivo microdialysis and AAV introduced forms of alpha-synuclein that are neurotoxic in vitro, and furthermore extends the hypothesis that macroautophagy can modulate alpha-synuclein release and uptake in vivo. Together, we will be able to determine which species of alpha-synuclein are released from cells and ultimately taken up by neighboring cells; the mechanisms associated with release and uptake; and if manipulations affecting alpha-synuclein release and uptake affect alpha-synuclein-induced toxicity in cells and animal models with the goal of translation into the clinic. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to investigate the impact of extracellular alpha-synuclein on neurodegeneration and disease progression in Parkinson's disease. Understanding extracellular alpha-synuclein biology may lead to the translation of new or different therapeutic approaches to halt or reverse disease progression in PD.

描述（由申请人提供）：本申请的目的是研究细胞外α-突触核蛋白对帕金森病（PD）神经变性和疾病进展的影响。以细胞外 α-突触核蛋白为目标来开发新型帕金森病治疗药物的原因有很多，其中包括在移植数年后，在帕金森病患者的健康移植神经元中发现了含有 α-突触核蛋白的路易体，这表明 α-突触核蛋白传播在疾病传播和进展中可能发挥作用。我们提出了补充方法，不仅阐明参与 α-突触核蛋白释放的基本机制和种类，而且开发针对细胞外 α-突触核蛋白寡聚体的独特治疗干预措施，以期了解细胞外 α-突触核蛋白生物学可以导致新的或不同的治疗方法的转化。我们将研究 3 个主要目标：第一个目标将使用一系列生物物理和分子工具来定义从神经元释放的 α-突触核蛋白的类型，这些工具可以表征释放的 α-突触核蛋白寡聚形式。我们还将研究涉及α-突触核蛋白释放和摄取的机制以及细胞外α-突触核蛋白对细胞活力的影响。第二个目标将扩展我们的初步研究和最近发表的研究，以调查涉及α-突触核蛋白释放和摄取的途径，特别是巨自噬在α-突触核蛋白释放和摄取中的作用。最后，第三个目标将这些观察扩展到体内，利用体内微透析和 AAV 引入的体外具有神经毒性的 α-突触核蛋白形式，并进一步扩展了巨自噬可以调节体内 α-突触核蛋白释放和摄取的假设。我们将共同确定哪些种类的 α-突触核蛋白从细胞中释放并最终被邻近细胞吸收；与释放和摄取相关的机制；影响α-突触核蛋白释放和摄取的操作是否会影响细胞和动物模型中α-突触核蛋白诱导的毒性，以转化为临床。 公共健康相关性：该提案的目的是研究细胞外 α-突触核蛋白对帕金森病神经变性和疾病进展的影响。了解细胞外 α-突触核蛋白生物学可能会导致新的或不同的治疗方法的转化，以阻止或逆转 PD 疾病进展。