ALPHA-SYNUCLEIN AND BRAIN CHOLESTEROL METABOLISM

α-突触核蛋白和脑胆固醇代谢

• 批准号: 7720890
• 负责人: ERIC James MURPHY
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720890
• 关键词: Adult; Alzheimer' s Disease; Amino Acids; Astrocytes; Atrophic; Brain; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Computer Retrieval of Information on Scientific Projects Database; Down Syndrome; Functional disorder; Funding; Genes; Grant; Institution; Lewy Body Disease; Link; Metabolism; Mutation; Neurodegenerative Disorders; Parkinson Disease; Physiological; Protein Overexpression; Proteins; Publishing; Research; Research Personnel; Resources; Site; Source; System; Testing; United States National Institutes of Health; Work; alpha synuclein; base; insight; nervous system disorder

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 is a 140 amino acid protein that is very abundant in the mammalian brain. Its overexpression and mutations in its gene are associated with familial Parkinson's disease. In addition, alpha-synuclein containing aggregates are also hallmarks of other neurological disorders, including the sporadic form of Parkinson's disease, Alzheimer's disease, Lewy body disease, Down's syndrome, and multiple-system atrophy, many of which are also associated with profound alterations in brain cholesterol homeostasis. Despite the association of alpha-synuclein with so many neurological disorders, its physiological function remains poorly described. We have recently demonstrated that alpha-synuclein expression impacts brain cholesterol and cholesteryl ester levels, however the mechanism(s) by which alpha-synuclein influences brain cholesterol and cholesteryl ester metabolism is unknown. In addition, we have observed an increase in astrocyte cholesterol and cholesteryl ester formation. This is especially important because astrocytes are the major site of cholesterol synthesis in the adult brain. Hence, this new link between alpha-synuclein and brain cholesterol metabolism is a critical observation because of the known association between brain cholesterol and neurodegenerative diseases. Understanding the mechanisms underlying this new link will provide significant, new insight into the pathophysiology of alpha-synuclein associated neurological disorders. Based upon our published work, our central hypothesis is that alpha-synuclein facilitates brain cholesterol metabolism by stimulating astrocyte cholesterol efflux and that in the absence of alpha-synuclein, cholesterol is trapped in the astrocyte leading to elevated brain cholesterol levels that are then stored as cholesteryl esters. This central hypothesis will be tested by the following specific aim: Determine the extent to which alpha-synuclein(snca) modulates brain cholesterol metabolism.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 α-突触核蛋白是一种由 140 个氨基酸组成的蛋白质，在哺乳动物大脑中含量非常丰富。 它的过度表达和基因突变与家族性帕金森病有关。 此外，含有α-突触核蛋白的聚集体也是其他神经系统疾病的标志，包括散发性帕金森病、阿尔茨海默病、路易体病、唐氏综合症和多系统萎缩症，其中许多疾病也与大脑胆固醇稳态的深刻改变有关。 尽管α-突触核蛋白与许多神经系统疾病有关，但其生理功能仍然知之甚少。 我们最近证明α-突触核蛋白表达会影响脑胆固醇和胆固醇酯水平，然而α-突触核蛋白影响脑胆固醇和胆固醇酯代谢的机制尚不清楚。 此外，我们还观察到星形胶质细胞胆固醇和胆固醇酯形成增加。 这一点尤其重要，因为星形胶质细胞是成人大脑中胆固醇合成的主要部位。 因此，由于脑胆固醇和神经退行性疾病之间已知的关联，α-突触核蛋白和脑胆固醇代谢之间的这种新联系是一个重要的观察结果。 了解这种新联系背后的机制将为α-突触核蛋白相关神经系统疾病的病理生理学提供重要的新见解。 根据我们发表的工作，我们的中心假设是α-突触核蛋白通过刺激星形胶质细胞胆固醇流出来促进脑胆固醇代谢，并且在缺乏α-突触核蛋白的情况下，胆固醇被困在星形胶质细胞中，导致脑胆固醇水平升高，然后以胆固醇酯的形式储存。 这一中心假设将通过以下具体目标进行检验：确定 α-突触核蛋白 (snca) 调节脑胆固醇代谢的程度。