MGH/MIT MORRIS UDALL CENTER OF EXCELLENCE IN PD RESEARCH

麻省总医院/麻省理工学院莫里斯尤德尔 PD 研究卓越中心

• 批准号: 7069474
• 负责人: ANNE B YOUNG
• 金额: $ 2.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069474
• 关键词: Parkinson' s disease; alpha synuclein; pathologic process

DESCRIPTION (provided by applicant): Recent discoveries have pointed to a central role of the protein alpha-synuclein in the etiology of Parkinson's disease and other synucleinopathies. The mechanism by which alpha-synuclein exerts a toxic effect is unknown. One potentially crucial mechanism is transcriptional dysregulation, meaning interference with the expression of cellular genes essential for normal function. Transcriptional dysregulation has been shown to be a key mechanism in other protein-aggregate neurodegenerative diseases including Alzheimer's disease and Huntington's disease. In the first three aims of this project we will address the question: Do alpha-synuclein aggregates lead to transcriptional dysregulation, either in dopaminergic neurons or their striatal targets? We will use an array-based approach to perform a broad examination of this question. In addition, we will conduct a focused study of two processes that may underlie the selective vulnerability of dopamine neurons characteristic of the disease: i) mechanisms for protection against oxidative stress, and ii) chaperone mechanisms for the degradation and clearance of misfolded proteins (in collaboration with Projects 2 and 4). A clearer understanding of the effects of alpha-synuclein on gene expression, oxidative stress and protein misfolding could lead to novel therapeutic strategies to prevent or retard this currently incurable disease. The fourth aim is directed at improving symptomatic therapy of the disease. The mainstay of existing therapies is dopaminergic replacement, but long-term use of these drugs is associated with adverse motor effects (wearing off and dyskinesia). In collaboration with Project 3, we will use gene expression studies to examine the striatal signaling pathways, which lead to these adverse effects, in search of new targets for symptomatic treatment.

描述（由申请人提供）： 最近的发现已经指出蛋白质α-突触核蛋白在帕金森病和其他突触核蛋白病的病因学中的中心作用。α-突触核蛋白发挥毒性作用的机制尚不清楚。一个潜在的关键机制是转录失调，这意味着干扰正常功能所必需的细胞基因的表达。转录失调已被证明是其他蛋白质聚集的神经退行性疾病，包括阿尔茨海默病和亨廷顿病的关键机制。在本项目的前三个目标，我们将解决的问题：α-突触核蛋白聚集体导致转录失调，无论是在多巴胺能神经元或其纹状体的目标？我们将使用基于数组的方法来对这个问题进行广泛的研究。此外，我们将进行两个过程的重点研究，这可能是疾病特征的多巴胺神经元的选择性脆弱性的基础：i）对氧化应激的保护机制，以及ii）降解和清除错误折叠蛋白质的分子伴侣机制（与项目2和4合作）。更清楚地了解α-突触核蛋白对基因表达，氧化应激和蛋白质错误折叠的影响可能会导致新的治疗策略，以预防或延缓这种目前无法治愈的疾病。第四个目标是改善疾病的对症治疗。现有治疗的主要方法是多巴胺能替代，但长期使用这些药物与不良运动效应（磨损和运动障碍）有关。与项目3合作，我们将使用基因表达研究来检查导致这些不良反应的纹状体信号通路，以寻找对症治疗的新靶点。