MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Parkinsons Dis. 2011;1(4):299-320.
Parkinson's disease, like many other neurodegenerative disorders, is characterized by the progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. The cascade by which the small synaptic protein α-synuclein misfolds to form distinctive protein aggregates, termed Lewy bodies and Lewy neurites, has been the subject of intensive research for more than a decade. Genetic and pathological studies in Parkinson's disease patients as well as experimental studies in disease models have clearly established altered protein metabolism as a key element in the pathogenesis of Parkinson's disease. Alterations in protein metabolism include misfolding and aggregation, post-translational modification and dysfunctional degradation of cytotoxic protein species. Protein folding and re-folding are both mediated by a highly conserved network of molecules, called molecular chaperones and co-chaperones. In addition to the regulatory role in protein folding, molecular chaperone function is intimately associated with pathways of protein degradation, such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway, to effectively remove irreversibly misfolded proteins. Because of the central role of molecular chaperones in maintaining protein homeostasis, we herein review our current knowledge on the involvement of molecular chaperones and co-chaperones in Parkinson's disease. We further discuss the capacity of molecular chaperones to prevent or modulate neurodegeneration, an important concept for future neuroprotective strategies and summarize the current progress in preclinical studies in models of Parkinson's disease and other neurodegenerative disorders. Finally we include a discussion on the future potential of using molecular chaperones as a disease modifying therapy.
帕金森病与许多其他神经退行性疾病一样，其特征是致病性蛋白物质的逐渐积累和细胞内包含体的形成。十多年来，α-突触核蛋白错误折叠形成独特的蛋白聚集体，称为路易小体和路易神经突的级联反应一直是密集研究的主题。帕金森病患者的遗传和病理学研究以及疾病模型中的实验研究清楚地确立了改变的蛋白质代谢是帕金森病发病机制的关键因素。蛋白质代谢的改变包括错误折叠和聚集、翻译后修饰以及细胞毒性蛋白的功能失调降解。蛋白质折叠和重折叠均由高度保守的分子网络（称为分子伴侣和共伴侣）介导。除了在蛋白质折叠中的调节作用外，分子伴侣的功能还与蛋白质降解途径密切相关，如泛素-蛋白酶体系统和自噬溶酶体途径，以有效去除不可逆错误折叠的蛋白质。由于分子伴侣在维持蛋白质内稳态中的核心作用，我们在此综述了我们目前对分子伴侣和共伴侣在帕金森病中的参与的了解。我们进一步讨论了分子伴侣预防或调节神经退行性变的能力，这是未来神经保护策略的一个重要概念，并总结了帕金森病和其他神经退行性疾病模型中的临床前研究的当前进展。最后，我们讨论了将分子伴侣用作疾病修饰治疗的未来潜力。
