Small Heat Shock Proteins in Parkinsons's Disease

帕金森病中的小热休克蛋白

• 批准号: 7386469
• 负责人: ANIL G CASHIKAR
• 金额: $ 7.35万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386469
• 关键词: Affect; Alexander Disease; Alzheimer' s Disease; Biochemical; Biological Models; Cell Culture System; Cells; Cessation of life; Chaperone Gene; Characteristics; Crystallins; Data; Deposition; Development; Disease; Equilibrium; Etiology; Failure; Functional disorder; Gene Targeting; Genes; Genetic Polymorphism; Goals; Heat shock proteins; Human; Impairment; Inclusion Bodies; Individual; Investigation; Knowledge; Lentivirus Vector; Lewy Bodies; Life; Localized; Location; Mediating; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Movement Disorders; Mus; Mutation; Myopathy; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neuropathy; Outcome; Parkinson Disease; Pathology; Protein Family; Proteins; Publications; Quality Control; Research; Research Personnel; Risk; Role; Severity of illness; Stress; Substantia nigra structure; System; Testing; Therapeutic; Thinking; Toxic effect; Ubiquitin; Work; age related; base; cytotoxicity; disorder risk; dopaminergic neuron; improved; innovation; motor disorder; multicatalytic endopeptidase complex; mutant; neurotoxic; neurotoxicity; novel; novel therapeutics; pars compacta; presynaptic; prevent; protective effect; protein aggregate; protein aggregation; protein function; protein misfolding; synuclein

DESCRIPTION (provided by applicant): Parkinson disease (PD) is a common neurodegenerative movement disorder characterized by an extensive and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. An emergent dogma applicable to PD and other neurodegenerative diseases is that neuronal dysfunction and death are mediated by protein aggregates, commonly known as 'oligomers'. Central to the pathophysiology of PD is a-synuclein (aSyn), an abundant presynaptic protein of unknown function. In both familial and 'sporadic' PD, aggregated aSyn deposits into intracellular fibrillar inclusions called Lewy bodies and Lewy neurites. Aggregated aSyn leads to an impairment of the ubiquitin-proteasome system resulting in accumulation of aSyn in model systems. The 'molecular chaperones' are a natural defense against protein misfolding and aggregation. Two molecular chaperones of the small heat shock proteins (sHsps) family, namely Hsp27 and aB-crystallin, are present in Lewy bodies. sHsps also provide strong protection in aSyn-mediated toxicity models. However, the mechanism of sHsp-mediated protective effect and its importance in Lewy body formation are not well understood. We have previously demonstrated that the sHsps function by forming co-assemblies with aggregation-prone proteins. Here, it is hypothesized that sHsps prevent toxicity of aSyn oligomers by co-assembling to form non-toxic inclusions (like Lewy bodies). We propose to test the effect of Hsp27 and aB-crystallin on the aggregation and toxicity of aSyn in a cell culture system. The proposed research will elucidate the molecular mechanisms of sHsps in regulating aSyn aggregation and its neurotoxicity thereby facilitating development of novel therapeutic strategies for PD. Parkinson's disease (PD) is the most common neurodegenerative motor disorder, which is characterized by the presence of Lewy bodies in dopaminergic neurons of substantia nigra. Despite the identification of several genes that increase the risk for PD, the disease mechanism is not well understood, thus hindering discovery of therapeutics. In this proposal we will examine the importance of an integral component of Lewy bodies, the small heat shock proteins, to illuminate novel therapeutic avenues.

描述（由申请人提供）：帕金森病（PD）是一种常见的神经退行性运动障碍，其特征是黑质致密部多巴胺能神经元广泛且进行性丧失。适用于帕金森病和其他神经退行性疾病的一个新兴教条是，神经元功能障碍和死亡是由蛋白质聚集体（通常称为“寡聚物”）介导的。 PD 病理生理学的核心是 a-突触核蛋白 (aSyn)，一种含量丰富但功能未知的突触前蛋白。在家族性和“散发性”帕金森病中，aSyn 聚集成细胞内纤维状包涵体，称为路易体和路易神经突。聚集的 aSyn 会导致泛素-蛋白酶体系统受损，导致模型系统中 aSyn 积累。 “分子伴侣”是针对蛋白质错误折叠和聚集的天然防御。小热休克蛋白 (sHsps) 家族的两个分子伴侣，即 Hsp27 和 aB-晶状体蛋白，存在于路易体中。 sHsps 还在 aSyn 介导的毒性模型中提供强有力的保护。然而，sHsp 介导的保护作用的机制及其在路易体形成中的重要性尚不清楚。我们之前已经证明，sHsps 通过与易于聚集的蛋白质形成共组装体来发挥作用。在此，假设 sHsps 通过共组装形成无毒内含物（如路易体）来防止 aSyn 寡聚物的毒性。我们建议在细胞培养系统中测试 Hsp27 和 aB-晶状体蛋白对 aSyn 的聚集和毒性的影响。拟议的研究将阐明 sHsps 调节 aSyn 聚集及其神经毒性的分子机制，从而促进开发新的 PD 治疗策略。 帕金森病（PD）是最常见的神经退行性运动障碍，其特征是黑质多巴胺能神经元中存在路易体。尽管已鉴定出几种增加帕金森病风险的基因，但对该疾病的机制尚不清楚，从而阻碍了治疗方法的发现。在本提案中，我们将研究路易体的一个组成部分（小型热休克蛋白）的重要性，以阐明新的治疗途径。