Folic Acid Improves Parkin-Null Phenotypes and Transiently Reduces Vulnerable Dopaminergic Neuron Mitochondrial Hydrogen Peroxide Levels and Glutathione Redox Equilibrium
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.
Drosophila, antioxidants, dopaminergic neuron, folic acid, glutathione, hydrogen peroxide, mitochondria, oxidative stress, parkin, roGFP
Antioxidants (Basel, Switzerland)
Digital Object Identifier (DOI)
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; and Buhlman, Lori M., "Folic Acid Improves Parkin-Null Phenotypes and Transiently Reduces Vulnerable Dopaminergic Neuron Mitochondrial Hydrogen Peroxide Levels and Glutathione Redox Equilibrium" (2022). Translational Neuroscience. 2259.