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: 9380682
• 负责人: Jennifer Rebecca Morgan
• 金额: $ 49.82万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380682
• 关键词: ATP phosphohydrolase; Acute; Address; Affect; Alzheimer' s Disease; Axon; Biochemical; Biological Assay; Brain; Clathrin; Coated vesicle; Cognitive deficits; Complement; Data; Defect; Dementia; Development; Dimerization; Disease; Disease Progression; Electrophysiology (science); Endocytosis; Functional disorder; Genetic; Goals; Human; Image; Impaired cognition; Impairment; In Vitro; Knowledge; Lampreys; Lewy Body Dementia; Link; Methods; Microinjections; Modeling; Molecular; Molecular Chaperones; Molecular Target; Molecular Weight; Nerve Degeneration; Neuromuscular Diseases; Neurons; Onset of illness; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Process; Proteins; Public Health; Reagent; Recycling; Reporting; Role; Stroke; Structure; Synapses; Synaptic Vesicles; Testing; Therapeutic; Toxic effect; Variant; Vesicle; Work; alpha synuclein; cellular targeting; complement C2a; design; dimer; experimental study; improved; in vivo; inhibitor/antagonist; innovation; insight; monomer; neurotransmission; overexpression; reagent testing; self assembly; spinal cord and brain injury; synaptic function; synuclein; targeted treatment; trafficking

The long term goal of this project is to identify the cellular and molecular mechanisms that give rise to the synaptic defects in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and variants of Alzheimer’s disease (AD) and to develop strategies for reversing them. A pathological hallmark of these diseases is aggregation of -synuclein throughout the neuron, including synapses. The synaptic aggregation of -synuclein is thought to be the cause of the cognitive deficits and dementia. While it is generally agreed that -synuclein accumulation at synapses impairs vesicle endocytosis, the underlying mechanisms remain unclear. Thus, at present, there are no known strategies for improving synaptic function in PD, DLB or AD because we don’t know the cellular or molecular targets. The proposed experiments take significant steps toward these goals by taking advantage of two classical vertebrate synapses that are ideally suited for studies on synaptic vesicle trafficking and by using both acute and genetic perturbations of -synuclein. The approach includes a combination of quantitative biochemical, electrophysiological, and imaging assays. One model for -synuclein toxicity suggests that it is initiated by formation of abnormal oligomers, while another proposes that build up of monomers is the trigger. Aim 1 will test predictions of both models at synapses by identifying how defined molecular species of -synuclein (monomers, dimers, higher molecular weight oligomers) affect vesicle trafficking and neurotransmission and the underlying mechanisms. Preliminary studies indicate that monomers and dimers produce distinct effects. Experiments in Aim 2 will determine the role for - synuclein self-association in producing synaptic defects by testing reagents that interfere with this process, including a drug with potential therapeutic value. Aim 3 is focused on reversing the synaptic defects caused by excess -synuclein by perturbing its association with Hsc70 chaperone protein, an idea that is supported by preliminary data. The experiments are innovative because they are the first to test the effects of defined molecular species of -synuclein at synapses, they continue the development of a new model synapse for these studies, and they will test several new reagents with potential for ameliorating the synaptic defects. The experiments are significant because they will elucidate the mechanisms by which excess-synuclein causes synaptic deficits, and they will provide possible targeted, molecular strategies for improving synaptic function. Thus, these studies have direct implications for slowing or halting the neurodegeneration, cognitive deficits, and dementia in PD, DLB and other related diseases.

该项目的长期目标是确定产生的细胞和分子机制 帕金森病 (PD)、路易体痴呆 (DLB) 和变体中的突触缺陷 阿尔茨海默病 (AD) 并制定逆转策略。病理学特征 这些疾病是 α-突触核蛋白在整个神经元（包括突触）中聚集造成的。突触 α-突触核蛋白的聚集被认为是认知缺陷和痴呆的原因。虽然它是 人们普遍认为，α-突触核蛋白在突触处的积累会损害囊泡内吞作用， 根本机制仍不清楚。因此，目前尚无已知的改善策略 PD、DLB 或 AD 中的突触功能，因为我们不知道细胞或分子靶标。这 所提出的实验通过利用两个经典的方法，朝着这些目标迈出了重要的一步 非常适合突触小泡运输研究的脊椎动物突触，并且通过使用两者 α-突触核蛋白的急性和遗传扰动。该方法包括定量相结合 生化、电生理学和成像测定。一种 α-突触核蛋白毒性模型表明 认为它是由异常低聚物的形成引发的，而另一种观点则提出， 单体是触发器。目标 1 将通过确定如何在突触处测试两种模型的预测 α-突触核蛋白的特定分子种类（单体、二聚体、较高分子量寡聚体）影响 囊泡运输和神经传递及其潜在机制。初步研究表明 单体和二聚体产生不同的效果。目标 2 中的实验将确定 α- 的作用 通过测试干扰突触核蛋白自关联产生突触缺陷的试剂 过程，包括具有潜在治疗价值的药物。目标 3 专注于逆转突触 过量的 α-突触核蛋白通过扰乱其与 Hsc70 伴侣蛋白的关联而引起缺陷， 初步数据支持的想法。这些实验具有创新性，因为它们是第一个 测试 α-突触核蛋白的特定分子种类对突触的影响，他们继续开发 用于这些研究的新模型突触，他们将测试几种具有潜力的新试剂 改善突触缺陷。这些实验很重要，因为它们将阐明 过量的α-突触核蛋白导致突触缺陷的机制，它们将提供可能的 改善突触功能的有针对性的分子策略。因此，这些研究具有直接 对减缓或阻止 PD、DLB 的神经退行性变、认知缺陷和痴呆的影响 以及其他相关疾病。