Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases

帕金森病和其他突触核蛋白相关疾病中突触功能障碍的机制

• 批准号: 10444260
• 负责人: Jennifer Rebecca Morgan
• 金额: $ 198.3万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444260
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Area; Binding; Biochemistry; Biological Process; Brain; Brain Diseases; Cells; Cognitive deficits; Data; Defect; Dementia with Lewy Bodies; Disease; Electrophysiology (science); Endocytosis; Event; Exhibits; Exocytosis; Functional disorder; Goals; Human; Impaired cognition; Impairment; In Vitro; Knowledge; Lampreys; Lewy Body Variant of Alzheimer' s Disease; Link; Membrane; Microinjections; Modeling; Modification; Molecular; Molecular Conformation; Molecular Probes; Molecular Weight; Nerve Degeneration; Neuromuscular Diseases; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Phenotype; Physiological; Post-Translational Protein Processing; Property; Proteins; Public Health; Reagent; Solubility; Stroke; Structure; Study models; Synapses; Synaptic Membranes; Synaptic Vesicles; Testing; Therapeutic; Toxic effect; Variant; Vesicle; Work; alpha synuclein; base; design; dimer; experimental study; improved; in vivo; inhibitor; insight; live cell imaging; monomer; neurotoxicity; novel; overexpression; predictive modeling; prevent; protein aggregation; reagent testing; small molecule; spinal cord and brain injury; synaptic function; synuclein; targeted treatment; therapy development; trafficking; treatment strategy

PROJECT ABSTRACT Aggregation of α-synuclein throughout the neuron, including at synapses, is a pathological hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and variants of Alzheimer’s disease (AD). Synaptic aggregation of α-synuclein is strongly associated with cognitive deficits and dementia in PD and DLB. The long-term goal of this project is to identify the cellular and molecular mechanisms that give rise to α-synuclein-induced synaptic deficits and to develop strategies for reversing them. While it is generally agreed that α-synuclein accumulation at synapses impairs synaptic vesicle trafficking, the underlying mechanisms remain unclear, preventing the development of treatments for improving synaptic function in PD and DLB. Over the last decade, we developed and implemented lamprey reticulospinal synapses as a new model for studying how α-synuclein accumulation impacts synapse structure and function. Our lab was the first to discover that acutely introducing excess α-synuclein to synapses, mimicking increased expression in PD and DLB, inhibits synaptic vesicle endocytosis. This result was subsequently corroborated at mammalian synapses. We then discovered that different molecular species of α-synuclein (e.g. monomers vs. dimers) cause distinct impacts on endocytosis, emphasizing the need to understand how each species affects synaptic vesicle trafficking and the underlying mechanisms. Experiments proposed here will significantly advance the field by: determining how post-translational modifications of α-synuclein alter its effects at synapses (Aim 1); identifying how α-synuclein oligomers purified from human PD and DLB brains affect synapses (Aim 2); and examining the underlying mechanisms with selective inhibitors of α-synuclein membrane binding and oligomerization (Aim 3). The project is significant because it will substantially increase our understanding of the impacts of excess α-synuclein on synapses, including pathology-associated strains, and it will provide initial testing of α-synuclein inhibitors with therapeutic potential while also probing the molecular mechanisms.

项目摘要 α-突触核蛋白在整个神经元中的聚集，包括在突触处，是 帕金森氏病(PD)、路易体痴呆(DLB)和阿尔茨海默病(AD)的变种。 α-突触核蛋白的突触聚集与帕金森病患者的认知障碍和痴呆密切相关 和DLB。该项目的长期目标是确定细胞和分子机制 引起α-突触核蛋白诱导的突触缺陷，并开发逆转这些缺陷的策略。当它 普遍认为，突触处α-突触核蛋白的积聚损害了突触小泡的运输， 潜在的机制仍不清楚，阻碍了改善治疗方法的开发 PD和DLB的突触功能。在过去的十年中，我们开发并实现了七鳃鳗 网状脊髓突触作为研究α-突触蛋白积聚影响突触的新模型 结构和功能。我们的实验室是第一个发现将过多的α-突触核蛋白引入 突触在PD和DLB中的表达增加，抑制突触小泡的内吞作用。这 这一结果随后在哺乳动物的突触中得到证实。然后我们发现不同的是 α-突触核蛋白的分子种类(例如，单体与二聚体)对内吞作用产生不同的影响， 强调有必要了解每个物种是如何影响突触囊泡运输的 潜在的机制。这里提出的实验将通过以下方式显著推进该领域：确定 α-突触核蛋白的翻译后修饰如何改变其对突触的影响(目标1)；确定如何 从人脑中提纯的α-突触核蛋白寡聚体影响突触(目标2)； α-突触核蛋白膜结合选择性抑制剂的作用机制 齐聚(目标3)。该项目意义重大，因为它将大大增加我们的 了解过量的α-突触核蛋白对突触的影响，包括与病理相关的影响 它将提供具有治疗潜力的α-突触核蛋白抑制剂的初步测试，同时还 探索分子机制。