MOLECULAR FUNCTION OF SYNUCLEIN

突触核蛋白的分子功能

• 批准号: 6611468
• 负责人: JULIA M GEORGE
• 金额: $ 29.92万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611468
• 关键词: Alzheimer's disease; Parkinson's disease; alpha synuclein; chimeric proteins; gene mutation; intermolecular interaction; membrane lipids; molecular pathology; neural degeneration; neural plasticity; phosphorylation; protein structure function; site directed mutagenesis; tissue /cell culture

DESCRIPTION (From the applicant's abstract): The long-term goal of this project is to define the normal and pathological roles of the synucleins, and in particular alpha-synuclein. Alpha-synuclein has emerged as a major focus of investigation because of an apparent (but poorly understood) role both in neurodegenerative disease and in normal synaptic plasticity and learning. The first aim for the next project period is to complete a formal biophysical characterization of human alpha-synuclein (halphaS), focusing on its ability to interact with membrane lipids and to self-associate. This aim will be conducted in collaboration with Dr. Seelig of the University of Basel. A second aim is to compare the properties of mutant synucleins linked to the development of Parkinson's disease, as well as a non-human (canary) alpha-synuclein, to gain insight into which features are specifically conserved and which may be more likely related to pathology. A third aim is to use site-directed mutagenesis to construct mutant forms of recombinant halphaS with altered lipid binding properties. This will provide insight into the functional organization of the sequence, and will generate mutant constructs potentially useful for probing synuclein's cellular functions. A fourth aim is to map the sites upon which synuclein is phosphorylated by the protein Casein Kinase II, and to investigate the structural and functional consequences of this modification on lipid binding and phospholipase D2 inhibition. A fifth aim will employ the various recombinant constructs produced and characterized in Aims 1-4, to probe the mechanisms by which synuclein can exert effects on cell function. In collaboration with Dr. Hyman of the Massachusetts General Hospital, the hypothesis that lipid binding is necessary for cell membrane association will be formally tested, and the necessity of lipid binding for both presynaptic terminal localization and PLD2 inhibition will also be tested. Collectively, these experiments test the hypothesis that synuclein's essential molecular function is related to its conserved structural features, which allow it to bind reversibly with intracellular membranes. Manipulation of these interactions could have uses in the development of therapies for age-related diseases including Alzheimer's and Parkinson's diseases.

描述（摘自申请人的摘要）：该项目的长期目标 是定义突触核素的正常和病理作用，在 特定的α-核蛋白。 α-突触核蛋白已成为 研究在 神经退行性疾病以及正常的突触可塑性和学习。这 下一个项目时期的第一个目标是完成正式的生物物理 人α-核蛋白的表征（Halphas），重点是其能力 与膜脂质相互作用并自我关联。这个目标将进行 与巴塞尔大学的Seelig博士合作。第二个目标是 比较突变突触蛋白的特性 帕金森氏病以及非人类（金丝雀）α-核蛋白，以获得 深入了解哪些功能是专门保存的，哪些特征可能更多 可能与病理有关。第三个目的是将定向的诱变用于 构建重组HANPHAS的突变形式，并改变脂质结合 特性。这将提供有关功能组织的见解 序列，并将生成可能对探测有用的突变构建体 突触核蛋白的细胞功能。第四个目标是绘制所在的地点 突触核蛋白被蛋白酪蛋白激酶II磷酸化，并研究 这种修饰在脂质上的结构和功能后果 结合和磷脂酶D2抑制。第五目标将采用各种 在目标1-4中产生和表征的重组结构，以探测 突触核素可以对细胞功能发挥影响的机制。在 与马萨诸塞州综合医院的海曼博士合作 假设脂质结合是细胞膜关联所必需的 进行正式测试，以及两种突触前的脂质结合的必要性 末端定位和PLD2抑制也将进行测试。共同 这些实验检验了突触核素必需分子的假设 功能与其保守的结构特征有关，这使其得以 用细胞内膜可逆地结合。操纵这些 互动可能用于开发与年龄有关的疗法 包括阿尔茨海默氏症和帕金森氏病在内的疾病。