Daher João Paulo Lima
Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
Neuroscience Research Australia, Barker St, Randwick, NSW, 2031, Australia.
Adv Neurobiol. 2017;14:209-226. doi: 10.1007/978-3-319-49969-7_11.
Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. It is best described as a movement disorder characterized by motor dysfunctions, progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, and abnormal intraneuronal protein aggregates, named Lewy bodies and Lewy neurites. Nevertheless, knowledge of the molecular events leading to this pathophysiology is incomplete. To date, only mutations in the α-synuclein and LRRK2-encoding genes have been associated with typical findings of clinical and pathologic PD. LRRK2 appears to have a central role in the pathogenesis of PD as it is associated with α-synuclein pathology and other proteins implicated in neurodegeneration. Thus, LRRK2 dysfunction may influence the accumulation of α-synuclein and its pathology through diverse pathomechanisms altering cellular functions and signaling pathways, including immune system, autophagy, vesicle trafficking, and retromer complex modulation. Consequently, development of novel LRRK2 inhibitors can be justified to treat the neurodegeneration associated with abnormal α-synuclein accumulation.
帕金森病（PD）是一种逐渐使人衰弱的神经退行性综合征。它最好被描述为一种运动障碍，其特征是运动功能障碍、黑质致密部多巴胺能神经元进行性退化以及异常的神经元内蛋白质聚集体，即路易小体和路易神经突。然而，导致这种病理生理学的分子事件的知识并不完整。迄今为止，仅α-突触核蛋白和LRRK2编码基因的突变与临床和病理PD的典型发现相关。LRRK2似乎在PD的发病机制中起核心作用，因为它与α-突触核蛋白病理学以及其他与神经退行性变有关的蛋白质相关。因此，LRRK2功能障碍可能通过改变细胞功能和信号通路的多种病理机制影响α-突触核蛋白的积累及其病理学，包括免疫系统、自噬、囊泡运输和逆转录复合物调节。因此，开发新型LRRK2抑制剂对于治疗与异常α-突触核蛋白积累相关的神经退行性变是合理的。
