Objective: We sought to determine whether the expression of PRKN, a young-onset Parkinson disease-linked gene, confers redox homeostasis in vivo.

Background: The mechanisms by which parkin protects the ageing human brain from developing Parkinson disease remain a topic of intense research activity.

Method: To test a role for parkin in redox homeostasis, we first combined the deletion of prkn with Sod2 haploinsufficiency in mice. Although adult, bigenic prkn^-/-//Sod2^+/- animals did not develop neuronal loss in the S. nigra (and thus did not develop parkinsonism), they had more reactive oxidative species and a higher concentration of carbonylated proteins in the midbrain. Because these redox changes were seen in the cytosol rather than mitochondria, we subsequently explored the thiol network in the context of PRKN expression.

Results: We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain and PRKN-linked human cortex. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione-reductase activity; it also altered activities (but not the concentration) of redox-sensitive enzymes in mitochondria from mouse brain: e.g., aconitase-2; creatine kinase. Intriguingly, human parkin itself showed glutathione-recycling activity in vitro: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S-glutathionylated by the other (GSSG + P-SH à GSH + P-S-SG), including at cysteines 59, 95 and 377. Moreover, parkin’s S-glutathionylation was reversible by glutaredoxin activity. In the absence of parkin, the activity of glutathione-reductase (but not the concentration of the protein) was increased by >30 per cent in homogenates of murine brain and human cortices.

Conclusion: In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, in part by participating in glutathione recycling, which involves a reversible posttranslational modification at select cysteines. Further, parkin’s impact on redox homeostasis in the cytosol alters mitochondrial enzyme activities in the brain. We posit that antioxidant functions of parkin could explain many previously described, protective effects in the nervous system of invertebrates and vertebrates that are not based on its E3 ligase activity.

References: Tokarew J et al., Acta Neuropathol. 2021
El Kodsi D et al., Acta Neuropathol Comm. 2023

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkin-coregulates-glutathione-metabolism-in-adult-brain-to-contribute-to-redox-homeostasis/