Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Mov Disord. 2018 May;33(5):717-729. doi: 10.1002/mds.27296. Epub 2018 Feb 8.
Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly α-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal α-synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society.
帕金森病的临床前研究主要依赖于小鼠和大鼠动物模型。最初，PD 动物模型主要通过化学神经毒素产生，这些毒素诱导黑质中多巴胺能神经元的急性丧失。在发现与 PD 有因果关系的遗传突变后，更多地使用小鼠而不是大鼠来生成携带 PD 相关突变的实验动物，因为大鼠中的诱变更为困难。哺乳动物基因组工程技术的最新进展和病毒表达载体的优化增加了 PD 遗传大鼠模型的使用。新兴的研究工具包括基因敲除大鼠，这些大鼠中的基因发生了突变，与 PD 有因果关系，包括 LRRK2、α-突触核蛋白、Parkin、PINK1 和 DJ-1。大鼠也越来越多地用于与 PD 相关的转基因和病毒介导的基因过表达，特别是 α-突触核蛋白。获得一个能够完全复制 PD 等复杂人类疾病的所有特征的单一动物模型可能并不现实。然而，与具有相同突变的小鼠相比，许多 PD 的遗传大鼠动物模型更好地复制了 PD 的关键方面，包括黑质中多巴胺能神经元的进行性丧失、运动行为缺陷以及年龄依赖性形成异常的 α-突触核蛋白蛋白聚集体。在这里，我们简要回顾了 PD 的遗传大鼠模型的新进展，这些进展可能具有更大的潜力来确定潜在的机制、发现新的治疗靶点，并开发急需的治疗方法来减缓或阻止疾病进展。 © 2018 国际帕金森病和运动障碍协会。
