Howard Hughes Medical Institute and Rockefeller University, New York, NY 10065, USA.
Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S185-8. doi: 10.1016/S1353-8020(09)70811-9.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selective and progressive degeneration of dopamine neurons in the substantia nigra. While most cases are sporadic a few rare familial forms of PD have been described. Several lines of evidence indicate that mitochondrial dysfunction may be involved in the etiology of the disease. Genes found to cause familial Parkinsonism have been linked to mitochondrial function and toxins that inhibit the mitochondrial respiratory chain have been found to cause dopamine cell death. Furthermore, higher numbers of respiratory chain deficient dopamine neurons are found in patients with PD than in age-matched controls. The MitoPark mouse model of PD was designed to directly test the hypothesis that mitochondrial dysfunction in dopamine neurons can cause a progressive parkinsonian phenotype. By cell type-specific inactivation of mitochondrial transcription factor A, a protein essential for mitochondrial DNA expression and maintenance, dopamine neurons were rendered respiratory chain deficient. MitoPark mice recapitulate several features of PD in humans such as adult-onset degeneration of nigrostriatal dopamine circuitry; motor deficits that are ameliorated by L-DOPA administration; progressive course of phenotypic manifestations and neurodegeneration; and altered response to L-DOPA treatment dependent on disease stage. In this review we compare the MitoPark mouse to other genetic or toxin-based rodent models of Parkinson's disease.
帕金森病(PD)是一种进行性神经退行性疾病,其特征是黑质中多巴胺神经元的选择性和进行性退化。虽然大多数病例是散发性的,但已经描述了少数罕见的家族性 PD 形式。有几条证据表明,线粒体功能障碍可能与疾病的病因有关。导致家族性帕金森病的基因与线粒体功能有关,并且已经发现抑制线粒体呼吸链的毒素会导致多巴胺神经元死亡。此外,与年龄匹配的对照组相比,PD 患者中呼吸链缺陷的多巴胺神经元数量更多。PD 的 MitoPark 小鼠模型旨在直接检验线粒体功能障碍在多巴胺神经元中是否会导致进行性帕金森表型的假设。通过线粒体转录因子 A 的细胞类型特异性失活,一种对线粒体 DNA 表达和维持至关重要的蛋白质,使多巴胺神经元失去呼吸链功能。MitoPark 小鼠重现了人类 PD 的几个特征,例如黑质纹状体多巴胺回路的成年发病性退化;左旋多巴给药可改善运动缺陷;表型表现和神经退行性变的进行性病程;以及对左旋多巴治疗的反应因疾病阶段而异。在这篇综述中,我们将 MitoPark 小鼠与其他基于遗传或毒素的 PD 啮齿动物模型进行了比较。