Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Human Metabolomics, North-West University, Potchefstroom, South Africa.
Mov Disord. 2021 Apr;36(4):815-831. doi: 10.1002/mds.28475. Epub 2021 Jan 29.
Over the past four decades, mitochondrial dysfunction has been a recurring theme in Parkinson's disease (PD) and is hypothesized to play a central role in its disease pathogenesis. Given the instrumental role of mitochondria in cellular energy production, their dysfunction can be detrimental to highly energy-dependent dopaminergic neurons, known to degenerate in PD. Mitochondria harbor multiple copies of their own genomes (mtDNA), encoding critical respiratory chain complexes required for energy production. Consequently, mtDNA has been investigated as a source of mitochondrial dysfunction in PD. As seen in multiple mitochondrial diseases, deleterious mtDNA variation and mtDNA copy number depletion can impede mtDNA protein synthesis, leading to inadequate energy production in affected cells and the onset of a disease phenotype. As such, high burdens of mtDNA defects but also mtDNA depletion, previously identified in the substantia nigra of PD patients, have been suggested to play a role in PD. Genetic variation in nuclear DNA encoding factors required for replicating, transcribing, and translating mtDNA, could underlie these observed mtDNA changes. Herein we examine this possibility and provide an overview of studies that have investigated whether nuclear-encoded genes associated with mtDNA processes may influence PD risk. Overall, pathway-based analysis studies, mice models, and case reports of mitochondrial disease patients manifesting with parkinsonism all implicate genes encoding factors related to mtDNA processes in neurodegeneration and PD. Most notably, cumulative genetic variation in these genes likely contributes to neurodegeneration and PD risk by acting together in common pathways to disrupt mtDNA processes or impair their regulation. © 2021 International Parkinson and Movement Disorder Society © 2021 International Parkinson and Movement Disorder Society.
在过去的四十年中，线粒体功能障碍一直是帕金森病（PD）的一个反复出现的主题，并被假设在其疾病发病机制中起核心作用。鉴于线粒体在细胞能量产生中的重要作用，其功能障碍可能对高度依赖能量的多巴胺能神经元有害，已知这些神经元在 PD 中会退化。线粒体拥有其自身基因组（mtDNA）的多个副本，这些基因编码产生能量所需的关键呼吸链复合物。因此，mtDNA 已被研究为 PD 中线粒体功能障碍的来源。如在多种线粒体疾病中所见，有害的 mtDNA 变异和 mtDNA 拷贝数耗竭会阻碍 mtDNA 蛋白合成，导致受影响细胞中的能量产生不足，并引发疾病表型。因此，先前在 PD 患者的黑质中发现的 mtDNA 缺陷和 mtDNA 耗竭的高负担被认为在 PD 中发挥作用。核 DNA 中编码复制、转录和翻译 mtDNA 所需因子的遗传变异可能是这些观察到的 mtDNA 变化的基础。在此，我们检查了这种可能性，并概述了研究核编码因子与 mtDNA 过程相关是否可能影响 PD 风险的研究。总体而言，基于途径的分析研究、小鼠模型和表现出帕金森病的线粒体疾病患者的病例报告都表明，编码与 mtDNA 过程相关的因子的基因参与了神经退行性变和 PD。值得注意的是，这些基因的累积遗传变异可能通过共同作用于破坏 mtDNA 过程或损害其调节的常见途径，共同导致神经退行性变和 PD 风险。© 2021 国际帕金森病和运动障碍学会© 2021 国际帕金森病和运动障碍学会。
