The heat shock protein 70 co-chaperone ST13 - a candidate disease-modifying gene for Parkinson disease

热休克蛋白 70 共伴侣 ST13——帕金森病的候选疾病修饰基因

• 批准号: 49516661
• 负责人: Dr. Gerrit Hennecke
• 金额: --
• 依托单位: Brigham and Womens Hospital
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/49516661?language=en
• 关键词: heat; shock; protein; 70; co

Parkinson’s disease (PD) is a neurodegenerative illness that affects five million people worldwide. In both idiopathic (sporadic) PD and familial PD caused by α-synuclein (SNCA) mutations, the pathologic hallmarks of the disease are large fibrillar α-synuclein-protein (αS) deposits (so called Lewy bodies) and degeneration of dopaminergic neurons in the substantia nigra. SNCA toxicity in cellular, yeast, and fly models of PD can be suppressed by a molecular chaperone, heat shock protein 70 (HSP70). Recently, my host laboratory found that in the substantia nigra of patients with PD, expression of HSP70 members is highly perturbed. Importantly, significant lower levels of the HSP70 co-chaperone ST13 were detected in blood of PD patients. Thus, we hypothesize that in common, sporadic PD reduced ST13 chaperone activity exacerbates αS aggregation and toxicity.I outline a research plan to (i) determine whether the co-chaperone ST13 suppresses α-synuclein aggregation and toxicity in cultured dopaminergic cells. (ii) I will precisely delineate changes in ST13 mRNA and protein expression in vulnerable dopaminergic neurons of the substantia nigra and in peripheral blood specimens of PD patients using kinetic, quantitative PCR, quantitative Western blotting, and immunohistochemistry. These studies will provide powerful new insights into the involvement of chaperones in the pathobiology of human PD.

帕金森病（PD）是一种神经退行性疾病，影响着全世界500万人。在由α-突触核蛋白（SNCA）突变引起的特发性（散发性）PD和家族性PD中，疾病的病理标志是大纤维状α-突触核蛋白（αS）沉积（所谓的路易体）和黑质多巴胺能神经元变性。SNCA在PD的细胞、酵母和苍蝇模型中的毒性可以被分子伴侣热休克蛋白70（HSP 70）抑制。最近，我所在的实验室发现，在PD患者的黑质中，HSP 70成员的表达受到高度干扰。重要的是，在PD患者的血液中检测到显著较低水平的HSP 70共伴侣ST 13。因此，我们假设，在共同的，散发性PD减少ST 13伴侣活性加剧αS聚集和toxicity.I概述了一项研究计划，以（i）确定是否co-chaperone ST 13抑制α-突触核蛋白聚集和毒性在培养的多巴胺能细胞。(ii)我将精确描绘ST 13 mRNA和蛋白表达的变化，在脆弱的黑质多巴胺能神经元和PD患者的外周血标本中使用动力学，定量PCR，定量Western印迹和免疫组化。这些研究将为分子伴侣参与人类PD的病理生物学提供强有力的新见解。