Mechanisms of synaptic dysfunction in Parkinson's and other synuclein-linked diseases

该项目的长期目标是确定引起细胞和分子机制， 帕金森氏病（PD）、路易体痴呆（DLB）和帕金森氏病（PD）的变体中的突触缺陷， 阿尔茨海默病（AD），并制定扭转他们的策略。这是一种病理学特征， 这些疾病是α-突触核蛋白在整个神经元（包括突触）中的聚集。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 普遍认为α-突触核蛋白在突触处的积累损害了囊泡的内吞作用， 潜在的机制仍不清楚。因此，目前，还没有已知的策略来改善 突触功能在PD，DLB或AD中的作用，因为我们不知道细胞或分子靶点。的 提出的实验通过利用两个经典的 脊椎动物突触，非常适合研究突触囊泡运输，并通过使用 α-突触核蛋白的急性和遗传扰动。该方法包括定量的 生物化学、电生理学和成像分析。一种α-突触核蛋白毒性模型表明， 它是由异常低聚物的形成引发的，而另一种观点认为， 单体是触发器。Aim 1将通过识别如何在突触上测试两种模型的预测， 定义的α-突触核蛋白分子种类（单体、二聚体、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- 突触核蛋白自缔合在产生突触缺陷中的作用， 包括具有潜在治疗价值的药物。目标3的重点是逆转突触 过量的α-突触核蛋白通过干扰其与Hsc 70伴侣蛋白的结合而引起的缺陷， 有初步数据支持的想法。这些实验是创新的，因为它们是第一个 为了测试α-突触核蛋白的特定分子种类在突触上的作用，他们继续开发 这些研究的新模型突触，他们将测试几种新的试剂， 改善突触缺陷。这些实验意义重大，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 改善突触功能的靶向分子策略。因此，这些研究直接 减缓或停止PD、DLB中的神经变性、认知缺陷和痴呆的意义 和其他相关疾病。

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 α-synuclein throughout the neuron, including synapses. The synaptic aggregation of α-synuclein is thought to be the cause of the cognitive deficits and dementia. While it is generally agreed that α-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 α-synuclein. The approach includes a combination of quantitative biochemical, electrophysiological, and imaging assays. One model for α-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 α-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 α- 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 α-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 α-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 α-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.