Houlihan Katherine L, Keoseyan Petros P, Juba Amber N, Margaryan Tigran, Voss Max E, Babaoghli Alexander M, Norris Justin M, Adrian Greg J, Tovmasyan Artak, Buhlman Lori M
Biomedical Sciences Program, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA.
Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
Antioxidants (Basel). 2022 Oct 20;11(10):2068. doi: 10.3390/antiox11102068.
Loss-of-function parkin mutations cause oxidative stress and degeneration of dopaminergic neurons in the substantia nigra. Several consequences of parkin mutations have been described; to what degree they contribute to selective neurodegeneration remains unclear. Specific factors initiating excessive reactive oxygen species production, inefficient antioxidant capacity, or a combination are elusive. Identifying key oxidative stress contributors could inform targeted therapy. The absence of parkin causes selective degeneration of a dopaminergic neuron cluster that is functionally homologous to the substantia nigra. By comparing observations in these to similar non-degenerating neurons, we may begin to understand mechanisms by which parkin loss of function causes selective degeneration. Using mitochondrially targeted redox-sensitive GFP2 fused with redox enzymes, we observed a sustained increased mitochondrial hydrogen peroxide levels in vulnerable dopaminergic neurons of parkin-null flies. Only transient increases in hydrogen peroxide were observed in similar but non-degenerating neurons. Glutathione redox equilibrium is preferentially dysregulated in vulnerable neuron mitochondria. To shed light on whether dysregulated glutathione redox equilibrium primarily contributes to oxidative stress, we supplemented food with folic acid, which can increase cysteine and glutathione levels. Folic acid improved survival, climbing, and transiently decreased hydrogen peroxide and glutathione redox equilibrium but did not mitigate whole-brain oxidative stress.
功能缺失的帕金森蛋白突变会导致黑质中多巴胺能神经元的氧化应激和退化。帕金森蛋白突变的几个后果已被描述；但它们在多大程度上导致选择性神经变性仍不清楚。引发过量活性氧产生、抗氧化能力低下或两者兼有的具体因素尚不清楚。确定关键的氧化应激因素可为靶向治疗提供依据。帕金森蛋白的缺失会导致与黑质功能同源的多巴胺能神经元簇的选择性退化。通过将这些观察结果与类似的未退化神经元进行比较，我们或许能够开始理解帕金森蛋白功能丧失导致选择性退化的机制。使用与氧化还原酶融合的线粒体靶向氧化还原敏感型绿色荧光蛋白2，我们观察到帕金森蛋白缺失果蝇的易损多巴胺能神经元中线粒体过氧化氢水平持续升高。在类似但未退化的神经元中仅观察到过氧化氢的短暂增加。脆弱神经元线粒体中的谷胱甘肽氧化还原平衡优先失调。为了弄清楚失调的谷胱甘肽氧化还原平衡是否主要导致氧化应激，我们在食物中添加了叶酸，叶酸可以增加半胱氨酸和谷胱甘肽水平。叶酸改善了果蝇的存活率、攀爬能力，并短暂降低了过氧化氢和谷胱甘肽氧化还原平衡，但并未减轻全脑氧化应激。
