Abstract

Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.

中文翻译：

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线粒体和帕金森病：临床、分子和转化方面

摘要

线粒体功能障碍是单基因和特发性帕金森病 (PD) 发病机制中公认的参与者。最初源于对线粒体毒素导致 PD 的观察，遗传 PD 的发现支持线粒体功能障碍对该疾病的贡献。在这里，由常染色体隐性遗传的 PD 基因Parkin、PTEN 诱导激酶 1 ( PINK1 ) 和DJ-1编码的蛋白质参与线粒体途径。线粒体功能障碍的其他证据源于常染色体显性 PD 模型，这是由于α-突触核蛋白( SNCA ) 和富含亮氨酸重复激酶 2 ( LRRK2 ) 的突变所致）。此外，携带线粒体聚合酶γ（POLG）改变的患者) 经常表现出帕金森症的迹象。虽然一些分子研究表明线粒体功能障碍是 PD 的主要事件，但其他人推测这是线粒体清除受损的结果。最近的研究甚至将非降解线粒体释放的损伤相关分子模式与 PD 的神经炎症过程联系起来。在这里，我们总结了在 PD 背景下处理线粒体的多种文献。此外，鉴于个性化医疗领域的最新进展，根据线粒体损伤程度对患者进行分层，然后进行线粒体增强治疗，可能至少有一部分遗传性和特发性 PD 病例具有潜力。因此，在本次审查的第二部分，