Small Heat Shock Proteins in Parkinsons's Disease

描述（由申请方提供）：帕金森病（PD）是一种常见的神经退行性运动障碍，其特征为黑质延髓部多巴胺能神经元的广泛和进行性损失。适用于PD和其他神经退行性疾病的一个新兴的教条是神经元功能障碍和死亡是由蛋白质聚集体介导的，通常称为“寡聚体”。PD的病理生理学的中心是α-突触核蛋白（aSyn），一种功能未知的丰富的突触前蛋白。在家族性和“散发性”PD中，聚集的aSyn沉积到称为路易体和路易神经突的细胞内纤维状内含物中。聚集的aSyn导致泛素-蛋白酶体系统的损伤，导致aSyn在模型系统中的积累。“分子伴侣”是防止蛋白质错误折叠和聚集的天然防御。Lewy小体中存在两种小分子热休克蛋白（small heat shock proteins，sHsps）家族的分子伴侣，即Hsp 27和aB-晶状体蛋白。sHsps还在aSyn介导的毒性模型中提供强保护。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还不清楚。我们以前已经证明，sHsps的功能，形成与聚集倾向的蛋白质的共组装。在此，假设sHsps通过共组装以形成无毒内含物（如路易体）来防止aSyn寡聚体的毒性。我们提出在细胞培养系统中测试Hsp 27和aB-晶状体蛋白对aSyn的聚集和毒性的影响。该研究将阐明sHsps调节aSyn聚集及其神经毒性的分子机制，从而促进PD新治疗策略的开发。 帕金森病（Parkinson 'sdisease，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内存在Lewy小体。尽管已经发现了几个增加PD风险的基因，但疾病机制尚未得到很好的理解，因此阻碍了治疗方法的发现。在这个建议中，我们将研究路易体的一个组成部分，小的热休克蛋白的重要性，照亮新的治疗途径。

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.