Lamberty Benjamin G, Estrella L Daniel, Mattingly Jane E, Emanuel Katy, Trease Andrew, Totusek Steven, Sheldon Lexi, George Joseph W, Almikhlafi Mohannad A, Farmer Trey, Stauch Kelly L
University of Nebraska Medical Center, College of Medicine, Department of Neurological Sciences, Omaha, NE, USA.
Brain Behav Immun Health. 2023 Jun 19;31:100656. doi: 10.1016/j.bbih.2023.100656. eCollection 2023 Aug.
Animal disease models are important for neuroscience experimentation and in the study of neurodegenerative disorders. The major neurodegenerative disorder leading to motor impairments is Parkinson's disease (PD). The identification of hereditary forms of PD uncovered gene mutations and variants, such as loss-of-function mutations in PTEN-induced putative kinase 1 (Pink1) and the E3 ubiquitin ligase Parkin, two proteins involved in mitochondrial quality control, that could be harnessed to create animal models. However, to date, such models have not reproducibly recapitulated major aspects of the disease. Here, we describe the generation and phenotypic characterization of a combined Pink1/Parkin double knockout (dKO) rat, which reproducibly exhibits PD-relevant abnormalities, particularly in male animals. Motor dysfunction in Pink1/Parkin dKO rats was characterized by gait abnormalities and decreased rearing frequency, the latter of which was responsive to levodopa treatment. Pink1/Parkin dKO rats exhibited elevated plasma levels of neurofilament light chain and significant loss of tyrosine hydroxylase expression in the substantia nigra pars compacta (SNpc). Glial cell activation was also observed in the SNpc. Pink1/Parkin dKO rats showed elevated plasma and reduced cerebrospinal levels of alpha-synuclein as well as the presence of alpha-synuclein aggregates in the striatum. Further, the profile of circulating lymphocytes was altered, as elevated CD3CD4 T cells and reduced CD3CD8 T cells in Pink1/Parkin dKO rats were found. This coincided with mitochondrial dysfunction and infiltration of CD3 T cells in the striatum. Altogether, the Pink1/Parkin dKO rats exhibited phenotypes similar to what is seen with PD patients, thus highlighting the suitability of this model for mechanistic studies of the role of Pink1 and Parkin in PD pathogenesis and as therapeutic targets.
动物疾病模型对于神经科学实验和神经退行性疾病的研究至关重要。导致运动障碍的主要神经退行性疾病是帕金森病（PD）。遗传性PD的鉴定揭示了基因突变和变体，例如磷酸酶及张力蛋白同源物诱导激酶1（Pink1）和E3泛素连接酶Parkin的功能丧失突变，这两种蛋白质参与线粒体质量控制，可用于创建动物模型。然而，迄今为止，此类模型尚未能可靠地重现该疾病的主要方面。在此，我们描述了一种联合的Pink1/Parkin双敲除（dKO）大鼠的产生及其表型特征，该大鼠可重现与PD相关的异常，特别是在雄性动物中。Pink1/Parkin dKO大鼠的运动功能障碍表现为步态异常和竖毛频率降低，后者对左旋多巴治疗有反应。Pink1/Parkin dKO大鼠血浆中神经丝轻链水平升高，黑质致密部（SNpc）中酪氨酸羟化酶表达显著丧失。在SNpc中也观察到胶质细胞活化。Pink1/Parkin dKO大鼠血浆中α-突触核蛋白水平升高，脑脊液中α-突触核蛋白水平降低，并且纹状体中存在α-突触核蛋白聚集体。此外，循环淋巴细胞的谱发生了改变，因为在Pink1/Parkin dKO大鼠中发现CD3CD4 T细胞升高而CD3CD8 T细胞减少。这与线粒体功能障碍和CD3 T细胞浸润到纹状体中相吻合。总之，Pink1/Parkin dKO大鼠表现出与PD患者相似的表型，从而突出了该模型对于研究Pink1和Parkin在PD发病机制中的作用以及作为治疗靶点的机制研究的适用性。
