Understanding the Molecular Origins of the Toxicity of Alpha-synuclein in Parkinson's Disease

帕金森病是一种进行性神经退行性疾病，占全球65岁以上人口的2%。人们普遍认为，帕金森病的特征是人α-突触核蛋白(一种突触前140个残基蛋白)的不溶性纤维沉积在路易体中。也有重要的遗传学证据表明α-突触核蛋白与帕金森病的发病机制有关，已知的点突变(A30P、E46K、H50Q、G51D和A53T)和基因三倍体可导致主要的遗传性早发性帕金森病。这一提议将最终理解前纤维α-突触核蛋白寡聚体毒性的结构基础，这些寡聚体被公认为帕金森病病因学中毒性最大的物种。由于这些蛋白质状态的瞬变性质，这是一个与重大实验和理论挑战相关的首要目标。事实上，目前对α-突触核蛋白寡聚体的性质，包括其毒性的结构和分子基础，缺乏了解。我们认为，我们的研究提议来得正是时候，因为我们现在拥有进行此类研究的所有工具。我们的目标是通过表征和比较两种形态相似但毒性水平显著不同的前纤维状低聚物的结构特性，揭示α-突触核蛋白低聚体细胞毒性的分子基础(Cremade等人，2012,149：1048-59)。通过使用溶液和固体核磁共振波谱并结合计算生物学，我们将确定这些低聚物的结构性质，并探讨它们与生物脂膜选择性相互作用的来源。我们的分析将扩展到α-突触核蛋白的病理突变，并将得到生物物理和细胞实验的补充。针对α-突触核蛋白低聚体/膜相互作用的分子基础的跨学科表征将对更广泛的学术界研究淀粉样蛋白疾病(包括帕金森氏症、阿尔茨海默氏症和II型糖尿病)的分子基础以及蛋白质科学、生物化学、核磁共振光谱、分子模拟、细胞和分子生物物理学等更广泛的学科产生重大影响。预计这项研究的结果可能会直接转化为知识，从而为帕金森氏病和其他淀粉样蛋白相关疾病提供新的治疗方法。

Parkinson's disease (PD) is a progressive neurodegenerative disorder afflicting 2% of the global population over 65 years of age. It is generally recognised that the hallmark of PD is the deposition of insoluble fibrils of human alpha-synuclein, a pre-synaptic 140-residue protein, in Lewy bodies. There is also significant genetic evidence implicating alpha-synuclein in the pathogenesis of PD, with point mutations (A30P, E46K, H50Q, G51D and A53T) and gene triplication known to cause dominantly inherited early onset PD.The proposal will achieve a conclusive understanding of the structural bases of the toxicity of prefibrilar alpha-synuclein oligomers, which are generally acknowledged to be the most toxic species in the aetiology of PD. This is a top goal that is associated with significant experimental and theoretical challenges owing to the transient nature of these protein states. Indeed, there is currently a poor understanding of the nature of alpha-synuclein oligomers, including the structural and molecular bases of their toxicity.We believe that our research proposal comes at a most opportune time, since we now have all the tools to perform such a study. Our goal is to unveil the molecular bases of the cellular toxicity of alpha-synuclein oligomers by characterising and comparing the structural properties of two types of pre-fibrilar oligomers having similar morphologies but significantly different levels of toxicity (Cremades et al Cell, 2012, 149:1048-59). By using solution and solid-state nuclear magnetic resonance (NMR) spectroscopy in combination with computational biology, we will determine the structural properties of these oligomers and investigate the origins of their selective interaction with biological lipid membranes. Our analysis will be extended to pathological mutants of alpha-synuclein and will be complemented by biophysical and cellular experiments. The aimed interdisciplinary characterisation of the molecular bases of alpha-synuclein oligomers/membrane interactions will have significant impact on the wider academic community studying the molecular bases of amyloid diseases (including Parkinson's, Alzheimer's and Diabetes type II) and wider disciplines such as protein science, biochemistry, NMR spectroscopy, molecular simulations, cellular and molecular biophysics. It is anticipated that the outcomes of this research may directly translate into knowledge leading to new therapeutic approaches in Parkinson's disease and other amyloid-associated disorders.