NEW INSIGHTS INTO THE STRUCTURAL PROPERTIES OF ALPHA-SYNUCLEIN AND ITS MUTANTS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 α-突触核蛋白（aS）是一种高度保守的突触前蛋白，参与突触强度维持和多巴胺稳态。它还参与在几个控制点调节细胞内多巴胺水平。 然而，aS淀粉样纤维的积累被认为是帕金森病发展的主要原因。α-突触核蛋白中的三个单点突变，即A30 P、A53 T和E46 K（以及aS基因的三倍）与罕见的帕金森病（PD）家族形式有关。另一方面，绝大多数路易体相关疾病病例是散发的，涉及野生型的aS。正常功能S涉及蛋白质与膜的相互作用，在此过程中，蛋白质经历了从胞质溶胶中的无序结构到膜结合状态中的高度螺旋结构的转变。脉冲偶极ESR已成功应用于表征与SDS胶束和磷脂膜结合的野生型aS的结构[1，2]。 我们对PD连锁突变体A30 P、E46 K和A53 T在膜结合状态下的结构特性进行了详细的研究，旨在阐明野生型aS及其PD连锁衍生物之间的最终差异。 后者可能对理解PD的发病机制有重要意义。 我们还研究了溶液中自由态的所有aS的结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alpha-synuclein (aS) is a highly conserved presynaptic protein that participates in synaptic strength maintenance and dopamine homeostasis. It is also involved in regulation of intracellular dopamine levels at several points of control. However, accumulation of aS amyloid fibrils was implicated as the major reason in the development of Parkinson's disease. The three single-point mutations in a-synuclein, namely, A30P, A53T, and E46K, (as well as a triplication of the aS gene) have been linked to a rare familial form of Parkinson's disease (PD). On the other hand the vast majority of Lewy body-related disease cases is sporadic and involves the wild type of aS. Normal functions of ¿S involve protein-membrane interactions upon which the protein undergoes transformations from disordered structure in cytosol to highly helical one in membrane-bound state. Pulsed dipolar ESR was already successfully applied to characterize the structure of wild type aS bound to SDS micelles and phispholipid membranes [1, 2]. We have undertaken a detailed study on the structural properties of PD-linked mutants A30P, E46K and A53T in membrane-bound state, aiming to elucidate eventual differences among wild type aS and its PD-linked derivates. The later might be important to understand the mechanism of PD. We also studied the structure of all aSs in free state in solution.