Bradford Xanthe, Fernandes Hugo J R, Snowden Stuart G
Department of Biological Sciences, Royal Holloway University of London, London TW20 0EX, UK.
Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK.
Antioxidants (Basel). 2024 Apr 24;13(5):508. doi: 10.3390/antiox13050508.
() is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology.
（）与神经退行性疾病的发展密切相关。除了驱动神经原纤维缠结（NFT）的形成外，该基因的突变还可通过线粒体超极化引起氧化应激。本研究探讨了该基因突变对诱导多能干细胞衍生的多巴胺神经元中磷脂代谢的影响，并确定这些影响是否因线粒体和内质网应激而加剧。具有该基因变异副本的神经元显示出比野生型神经元显著更高水平的氧化磷脂（Oxo-PL）。疏水脂肪酸侧链的氧化改变了磷脂的化学性质，导致膜功能破坏和潜在的细胞裂解。在野生型神经元中，线粒体和内质网应激均增加了Oxo-PL的丰度；然而，在该基因突变神经元中，线粒体应激似乎影响最小。令人惊讶的是，内质网应激降低了该基因突变多巴胺神经元中Oxo-PL的丰度，我们推测这种降低可能通过未折叠蛋白反应和X盒结合蛋白1的过度激活来调节。总体而言，本研究结果有助于进一步加深我们对帕金森病病理学中氧化应激调节及其影响的理解。
