Airavaara Mikko, Parkkinen Ilmari, Konovalova Julia, Albert Katrina, Chmielarz Piotr, Domanskyi Andrii
Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.
Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
Curr Protoc Neurosci. 2020 Mar;91(1):e88. doi: 10.1002/cpns.88.
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non-motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α-synuclein, LRRK2, DJ-1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α-synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD-like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector-mediated transgene expression and, recently, injections of misfolded α-synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre-clinical PD research towards successful disease-modifying therapy. © 2020 The Authors.
帕金森病（PD）是一种与年龄相关的神经退行性疾病，其特征包括震颤、运动迟缓、僵硬和姿势不稳等运动症状，以及睡眠障碍、嗅觉丧失、抑郁、便秘和疼痛等非运动特征。运动症状是由于黑质致密部多巴胺能神经元逐渐丧失，导致纹状体中多巴胺耗竭所致。约10%的帕金森病病例为家族性，由α-突触核蛋白、LRRK2、DJ-1、PINK1、parkin和其他几种蛋白质的基因突变引起。然而，大多数帕金森病病例是特发性的，即没有明确的病因。帕金森病的特征是不可溶性包涵体（称为路易小体）的逐渐积累，其主要由α-突触核蛋白和膜成分组成。目前，帕金森病的病因被认为是细胞蛋白质稳态失调和线粒体功能障碍，这两者可能相互依存。此外，帕金森病患者大脑中存在神经炎症，但其是神经退行性变的原因还是结果仍有待研究。啮齿动物不会自发出现帕金森病或类似帕金森病的运动症状；然而，神经毒素、基因突变、病毒载体介导的转基因表达以及最近注射错误折叠的α-突触核蛋白已成功用于模拟该疾病的某些方面。在此，我们批判性地回顾了啮齿动物帕金森病模型的优缺点，并讨论了推进临床前帕金森病研究以实现成功的疾病修饰治疗的方法。© 2020作者。
