Volpicelli-Daley Laura A, Kirik Deniz, Stoyka Lindsay E, Standaert David G, Harms Ashley S
From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama.
Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, Lund, Sweden.
J Neurochem. 2016 Oct;139 Suppl 1(Suppl 1):131-155. doi: 10.1111/jnc.13627. Epub 2016 May 4.
Animal models of Parkinson's disease (PD) are important for understanding the mechanisms of the disease and can contribute to developing and validating novel therapeutics. Ideally, these models should replicate the cardinal features of PD, such as progressive neurodegeneration of catecholaminergic neurons and motor defects. Many current PD models emphasize pathological forms of α-synuclein, based on findings that autosomal dominant mutations in α-synuclein and duplications/triplications of the SNCA gene cause PD. In addition, Lewy bodies and Lewy neurites, primarily composed of α-synuclein, represent the predominant pathological characteristics of PD. These inclusions have defined features, such as insolubility in non-ionic detergent, hyperphosphorylation, proteinase K sensitivity, a filamentous appearance by electron microscopy, and β-sheet structure. Furthermore, it has become clear that Lewy bodies and Lewy neurites are found throughout the peripheral and central nervous system, and could account not only for motor symptoms, but also for non-motor symptoms of the disease. The goal of this review is to describe two new α-synuclein-based models: the recombinant adeno-associated viral vector-α-synuclein model and the α-synuclein fibril model. An advantage of both models is that they do not require extensive crossbreeding of rodents transgenic for α-synuclein with other rodents transgenic for genes of interest to study the impact of such genes on PD-related pathology and phenotypes. In addition, abnormal α-synuclein can be expressed in brain regions relevant for disease. Here, we discuss the features of each model, how each model has contributed thus far to our understanding of PD, and the advantages and potential caveats of each model. This review describes two α-synuclein-based rodent models of Parkinson's disease: the rAAV-α-synuclein model and the α-synuclein fibril model. The key features of these models are described, and the extent to which they recapitulate features of PD, such as α-synuclein inclusion formation, loss of dopaminergic synapses in the striatum, motor defects, inflammation, and dopamine neuron death. This article is part of a special issue on Parkinson disease.
帕金森病（PD）动物模型对于理解该疾病的发病机制至关重要，有助于开发和验证新的治疗方法。理想情况下，这些模型应复制PD的主要特征，如儿茶酚胺能神经元的进行性神经变性和运动缺陷。基于α-突触核蛋白的常染色体显性突变以及SNCA基因的重复/三倍体导致PD这一发现，许多当前的PD模型都强调α-突触核蛋白的病理形式。此外，主要由α-突触核蛋白组成的路易小体和路易神经突是PD的主要病理特征。这些包涵体具有明确的特征，如在非离子去污剂中不溶、过度磷酸化、对蛋白酶K敏感、电子显微镜下呈丝状外观以及β-折叠结构。此外，现已明确路易小体和路易神经突存在于外周和中枢神经系统各处，不仅可导致运动症状，还可引发该疾病的非运动症状。本综述的目的是描述两种基于α-突触核蛋白的新模型：重组腺相关病毒载体-α-突触核蛋白模型和α-突触核蛋白原纤维模型。这两种模型都具有一个优点，即它们不需要将α-突触核蛋白转基因的啮齿动物与其他感兴趣基因的转基因啮齿动物进行广泛的杂交育种，以研究此类基因对PD相关病理和表型的影响。此外，异常的α-突触核蛋白可以在与疾病相关的脑区表达。在此，我们讨论每种模型的特征、每种模型到目前为止对我们理解PD所做的贡献以及每种模型的优点和潜在的注意事项。本综述描述了两种基于α-突触核蛋白的帕金森病啮齿动物模型：rAAV-α-突触核蛋白模型和α-突触核蛋白原纤维模型。描述了这些模型的关键特征，以及它们重现PD特征的程度，如α-突触核蛋白包涵体形成、纹状体中多巴胺能突触丧失、运动缺陷、炎症和多巴胺神经元死亡。本文是帕金森病特刊的一部分。
