Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
J Parkinsons Dis. 2011;1(3):229-51. doi: 10.3233/JPD-2011-11041.
Parkinson's disease is a common neurodegenerative disorder whose aetiology is not yet fully understood. In the past ten years, the discovery of genes linked to hereditary forms of the disease has impelled the development of animal models. These should lead to the identification of novel pathways that provide insight into the functionality of the proteins involved and the pathogenesis of the sporadic forms of the disease. In particular, loss-of-function mutations in the parkin and PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1) genes account for most of the cases of familial autosomal recessive parkinsonism. Both parkin and PINK1 knockout rodent models are now available, which display an overall mild phenotype consisting of a mitochondrial dysfunction together with changes in dopamine metabolism and oxidative stress. However, up till now these models fail to reproduce the main hallmarks of Parkinson's disease: the dopaminergic cell loss in the substantia nigra and the presence of cytoplasmic inclusions, named Lewy bodies, in the remaining dopaminergic neurons. We here review the most important knockout and knockdown rodent models generated so far for these two recessive Parkinson's disease-causing genes. We critically feature their main characteristics and their impact on the research field, and propose some future directions for the study and modelling of the loss of function of parkin and PINK1 in rodents.
帕金森病是一种常见的神经退行性疾病，其病因尚未完全阐明。在过去的十年中，与遗传性疾病相关的基因的发现推动了动物模型的发展。这些模型应该能够识别新的途径，深入了解相关蛋白的功能以及散发性疾病的发病机制。特别是，parkin 和 PINK1（磷酸酶和张力蛋白同源物（PTEN）诱导的激酶 1）基因的功能丧失性突变占家族性常染色体隐性帕金森病的大多数病例。现在已经有 parkin 和 PINK1 基因敲除的啮齿动物模型，这些模型表现出一种整体的轻度表型，包括线粒体功能障碍以及多巴胺代谢和氧化应激的变化。然而，到目前为止，这些模型未能再现帕金森病的主要特征：黑质中多巴胺能神经元的丧失以及剩余多巴胺能神经元中细胞质包涵体（称为路易体）的存在。我们在这里回顾了迄今为止为这两个隐性帕金森病致病基因生成的最重要的基因敲除和基因敲低啮齿动物模型。我们批判性地介绍了它们的主要特征及其对研究领域的影响，并为研究和模拟 parkin 和 PINK1 在啮齿动物中的功能丧失提出了一些未来的方向。
