Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Human Medicine, Medical School Hamburg, Hamburg, Germany.
Biochem Biophys Res Commun. 2020 May 7;525(3):570-575. doi: 10.1016/j.bbrc.2020.02.106. Epub 2020 Feb 27.
Retrotransposon activation occurs in a variety of neurological disorders including multiple sclerosis and Alzheimer's Disease. While the origins of disease-related retrotransposon activation have remained mostly unidentified, this phenomenon may well contribute to disease progression by inducing inflammation, disrupting transcription and, potentially, genomic insertion. Here, we report that the inhibition of mitochondrial respiratory chain complex I by pharmacological agents widely used to model Parkinson's disease leads to a significant increase in expression of the ORF1 protein of the long interspersed nucleotide element 1 (LINE1) retrotransposon in human dopaminergic LUHMES cells. These findings were recapitulated in midbrain lysates from accordingly treated wild-type mice that mimic Parkinson's disease. Retrotransposon activation was paralleled by a loss of DNA cytosine methylation, providing a potential mechanism of retrotransposon mobilization. Loss of DNA methylation as well as retrotransposon activation were suppressed by the mitochondrial antioxidant phenothiazine, indicating that the well-established production of oxidants by inhibited complex I was causing these effects. Retrotransposon activation in some brain disorders may be less of a primary disease trigger rather than a consequence of mitochondrial distress, which is very common in neurodegenerative diseases.
逆转录转座子的激活发生在多种神经紊乱疾病中，包括多发性硬化症和阿尔茨海默病。虽然与疾病相关的逆转录转座子激活的起源在很大程度上仍未被识别，但这种现象可能通过诱导炎症、扰乱转录，并且可能通过基因组插入，从而促进疾病进展。在这里，我们报告称，广泛用于模拟帕金森病的药物抑制线粒体呼吸链复合物 I 会导致人类多巴胺能 LUHMES 细胞中长散布核苷酸元件 1（LINE1）逆转录转座子的 ORF1 蛋白表达显著增加。在相应治疗的模拟帕金森病的野生型小鼠的中脑匀浆中重现了这些发现。逆转录转座子的激活伴随着 DNA 胞嘧啶甲基化的丧失，为逆转录转座子的动员提供了潜在的机制。线粒体抗氧化剂吩噻嗪抑制了 DNA 甲基化的丧失和逆转录转座子的激活，表明被抑制的复合物 I 产生的氧化应激物质导致了这些影响。在一些脑紊乱疾病中，逆转录转座子的激活可能不是疾病的主要触发因素，而是线粒体损伤的结果，而线粒体损伤在神经退行性疾病中非常普遍。
