Snyder Heather, Wolozin Benjamin
Boston University School of Medicine, 715 ALbany Street, Room L-603, Boston, MA 02118-2526, USA.
J Mol Neurosci. 2004;24(3):425-42. doi: 10.1385/JMN:24:3:425.
Parkinson's disease (PD) is a multifactorial disease that appears to arise from the effects of both genetic and environmental influences. Pesticides and heavy metals are the principle environmental factors that appear to impact on PD. The known genetic factors include multiple genes that have been identified in related parkinsonian syndromes, as well as alpha-synuclein. Genes associated with either PD or Parkinson-related disorders include parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), nuclear receptor-related factor 1, and alpha-synuclein. Alpha-synuclein is particularly notable because it aggregates readily and is the main component of Lewy bodies (LBs). Aggregated alpha-synuclein binds the proteasome and potently inhibits proteasomal activity. Because ubiquitin accumulates in LBs, and parkin and UCH-L1 also interact with the ubiquitin proteasomal system, proteasomal dysfunction is thought to contribute to the pathophysiology of PD. Increasing numbers of experiments suggest that neurotoxins might interact with alpha-synuclein or other Parkinson-related proteins to contribute to the pathophysiology of PD. Transgenic animal models overexpressing alpha-synuclein develop age-dependent motor dysfunction and inclusions in the brain stem that contain alpha-synuclein. These models are very helpful in elucidating the pathophysiology of PD but do not completely recapitulate the disease process. The relationship between these transgenic models and PD is a subject of intense investigation.
帕金森病（PD）是一种多因素疾病，似乎由遗传和环境影响共同作用引起。农药和重金属是似乎对帕金森病有影响的主要环境因素。已知的遗传因素包括在相关帕金森综合征中已鉴定出的多个基因，以及α-突触核蛋白。与帕金森病或帕金森相关疾病相关的基因包括帕金蛋白、DJ-1、泛素C末端水解酶同工酶L1（UCH-L1）、核受体相关因子1和α-突触核蛋白。α-突触核蛋白特别值得注意，因为它容易聚集，并且是路易小体（LBs）的主要成分。聚集的α-突触核蛋白与蛋白酶体结合并强烈抑制蛋白酶体活性。由于泛素在路易小体中积累，并且帕金蛋白和UCH-L1也与泛素蛋白酶体系统相互作用，因此蛋白酶体功能障碍被认为是帕金森病病理生理学的一个因素。越来越多的实验表明，神经毒素可能与α-突触核蛋白或其他帕金森相关蛋白相互作用，从而导致帕金森病的病理生理学变化。过度表达α-突触核蛋白的转基因动物模型会出现年龄依赖性运动功能障碍以及脑干中含有α-突触核蛋白的包涵体。这些模型在阐明帕金森病的病理生理学方面非常有帮助，但并未完全重现疾病过程。这些转基因模型与帕金森病之间的关系是一个深入研究的课题。
