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）： 最近的发现表明，蛋白质α-核蛋白在帕金森氏病和其他突触核酸病毒病因中的核心作用。 α-突触核蛋白发挥毒性作用的机制尚不清楚。一种潜在的至关重要的机制是转录失调，意味着干扰正常功能必不可少的细胞基因的表达。转录失调已被证明是其他蛋白质聚集的神经退行性疾病的关键机制，包括阿尔茨海默氏病和亨廷顿氏病。在该项目的前三个目标中，我们将解决一个问题：α-突触核蛋白聚集体是否导致转录失调，无论是多巴胺能神经元还是其纹状体靶标？我们将使用基于阵列的方法对此问题进行广泛的检查。此外，我们将对两种过程进行重点研究，这些过程可能是该疾病特征的多巴胺神经元特征的选择性脆弱性的基础：i）保护抗氧化应激的机制，ii）II）伴侣机制的机制，用于降解和清除错误折叠蛋白的蛋白质（与项目2和4合作）。对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有更清晰的了解可能导致预防或阻碍这种目前无法治愈的疾病的新型治疗策略。第四个目标旨在改善对疾病的症状治疗。现有疗法的支柱是多巴胺能的替代品，但这些药物的长期使用与不良运动效应（磨损和运动障碍）有关。通过与项目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传导途径，以寻找新的症状治疗靶标。