Parkinson’s disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer’s disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and α-synuclein (αS) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age-dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal αS pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin–proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between αS aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD.

帕金森氏病（PD）是成年人的慢性进行性运动障碍，是仅次于阿尔茨海默氏病的第二大最常见的神经退行性疾病。PD的神经病理学诊断需要在腹侧黑质致密部和α-突触核蛋白（αS）路易氏体病理中中度至明显神经元丢失。黑质纹状体多巴胺能神经退行性变与帕金森氏运动特征有关，但其他周围和中枢神经系统区域的参与会导致广泛的非运动特征。黑质纹状体多巴胺能神经退行性变与其他帕金森病（包括某些遗传形式的帕金森病）共有，但许多此类疾病没有路易体。因此，理想的PD动物模型应表现出年龄依赖性和进行性的多巴胺能神经退行性疾病，运动功能障碍和异常的αS病理。在过去的几十年中，使用基于遗传或毒素的策略的PD啮齿动物模型已广泛用于研究PD的发病机理和治疗方法，但很少能概括PD的所有主要临床和病理特征。新的策略或对基本疾病过程的更好理解可能会促进更好的动物模型的发展。在这篇综述中，我们重点介绍了基于四种主要细胞功能受损的PD啮齿动物模型的开发进展：线粒体氧化磷酸化，自噬-溶酶体代谢，泛素-蛋白酶体蛋白降解以及内质网应激/未折叠蛋白反应。我们试图评估这些主要细胞系统的损伤如何导致PD，以及如何在啮齿动物模型中利用它们。此外，我们回顾了最近的细胞生物学研究，这些研究表明αS聚集与核膜完整性受损之间存在联系，正如在细胞凋亡的细胞模型中观察到的那样。我们还简要讨论了吞噬清除能力不全的作用，以及在开发新的PD啮齿动物模型时应如何考虑这一因素。