α-突触核蛋白多聚体与神经囊泡相互作用的分子机制及在帕金森病中的病理意义

Neurodegenerative diseases are a type of disease in which the latency and the onset period are very long. So far, there is no effective treatment, which brings great mental and economic burden to patients, their family members , as well as the society. It has been shown that several protein markers in neurodegenerative diseases affect the process of SNARE-mediated neurotransmitters release. The mechanism investigation of interrelationship between these protein marker has become a worldwide hot spot. Applicant took neurotransmitter release as a model to reconstitute and mimic the process of SNARE-mediated neurotransmitter release in vitro, and systematically studied the molecule mechanism of complexin, Munc13 and other regulatory proteins in the regulation of neurotransmitter release. Recent studies have shown that α-synuclein and its multimers have important regulatory roles in neurotransmission, but the molecular mechanisms of its multimerization and regulation of neurotransmission remain unclear. Applicant plans to combine the biophysical and cell biology experimental methods to study the mechanism of α-synuclein multimerization and their physiological functions and pathotoxicity.

神经退行性疾病是一类临床前期和发病期都十分漫长的疾病，至今尚无有效治疗手段，给病人，病人家属和社会带来了极大的精神和经济负担。研究表明，神经退行性疾病中若干标志蛋白分子，不同程度的影响了有SNARE蛋白介导的神经递质的释放过程。它们之间的相互关联和机制研究已经成为国际研究的热点。申请人以神经递质释放为模型，实现了在体外重组和模拟SNARE蛋白介导的神经递质释放的过程，并系统深入地研究了complexin，Munc13等调控蛋白在调控神经递质释放过程中的分子机制。近期实验显示α-突触核蛋白及其多聚体在神经信号传导过程中的有重要调节作用, 但是其多聚化和调控神经信号传导的分子机理仍不清楚。申请人希望能结合生物物理和细胞生物学实验手段来研究α-突触核蛋聚合机理以及它们的生理功能及病理毒性。

α-突触核蛋白（α-Synuclein，α-Syn）是一种140氨基酸的胞质蛋白，在神经元细胞中含量丰富，主要定位于突触前末端和核周区域。三种人类神经退行性疾病：帕金森病（PD），路易体痴呆（DLB）和多系统萎缩（MSA）都是由聚集的α-Syn组成的细胞内蛋白质沉积物的积累所引起的。路易体（Lewy bodies，LBs）由α-Syn组成，构成脑中PD的主要组织病理学特征。α-Syn本质上是无序的单体，并且在与脂质膜结合时转变为α-螺旋，这一特征被认为与蛋白质的正常功能有关。过去，我们的研究发现α-Syn可以导致突触囊泡的蛋白脂质体聚集，而这取决于α-Syn与阴离子磷脂的特定相互作用。在这里，我们发现中性磷脂溶血磷脂酰胆碱（LysoPC）在突触体中富集，并且α-Syn与之具有相互作用。即使在没有阴离子脂质的情况下，LysoPC也可以促进α-Syn介导的囊泡聚集，但在单囊泡融合实验中发现其对Ca2+的触发融合没有影响。导致家族性帕金森病的α-Syn A30P突变体可能破坏与LysoPC的相互作用以及突触囊泡的聚集。总之，α-Syn-LysoPC相互作用可能在α-Syn的功能中发挥作用。