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Open Access 01-12-2023 | Parkinson's Disease | Research

Parkin coregulates glutathione metabolism in adult mammalian brain

Authors: Daniel N. El Kodsi, Jacqueline M. Tokarew, Rajib Sengupta, Nathalie A. Lengacher, Ajanta Chatterji, Angela P. Nguyen, Heather Boston, Qiubo Jiang, Carina Palmberg, Chantal Pileggi, Chet E. Holterman, Bojan Shutinoski, Juan Li, Travis K. Fehr, Matthew J. LaVoie, Rajiv R. Ratan, Gary S. Shaw, Masashi Takanashi, Nobutaka Hattori, Christopher R. Kennedy, Mary-Ellen Harper, Arne Holmgren, Julianna J. Tomlinson, Michael G. Schlossmacher

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

We recently discovered that the expression of PRKN, a young-onset Parkinson disease-linked gene, confers redox homeostasis. To further examine the protective effects of parkin in an oxidative stress model, we first combined the loss of prkn with Sod2 haploinsufficiency in mice. Although adult prkn^−/−//Sod2^± animals did not develop dopamine cell loss in the S. nigra, they had more reactive oxidative species and a higher concentration of carbonylated proteins in the brain; bi-genic mice also showed a trend for more nitrotyrosinated proteins. Because these redox changes were seen in the cytosol rather than mitochondria, we next explored the thiol network in the context of PRKN expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, PRKN-linked human cortex and several cell models. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione reductase activity; it also correlated with altered activities of redox-sensitive enzymes in mitochondria isolated from mouse brain (e.g., aconitase-2; creatine kinase). Intriguingly, human parkin itself showed glutathione-recycling activity in vitro and in cells: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S-glutathionylated by the other (GSSG + P-SH \(\to\) GSH + P-S-SG), including at cysteines 59, 95 and 377. Moreover, parkin’s S-glutathionylation was reversible by glutaredoxin activity. In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, including by parkin’s participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin’s impact on redox homeostasis in the cytosol can affect enzyme activities elsewhere, such as in mitochondria. We posit that antioxidant functions of parkin may explain many of its previously described, protective effects in vertebrates and invertebrates that are unrelated to E3 ligase activity.

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Title: Parkin coregulates glutathione metabolism in adult mammalian brain
Authors: Daniel N. El Kodsi
Jacqueline M. Tokarew
Rajib Sengupta
Nathalie A. Lengacher
Ajanta Chatterji
Angela P. Nguyen
Heather Boston
Qiubo Jiang
Carina Palmberg
Chantal Pileggi
Chet E. Holterman
Bojan Shutinoski
Juan Li
Travis K. Fehr
Matthew J. LaVoie
Rajiv R. Ratan
Gary S. Shaw
Masashi Takanashi
Nobutaka Hattori
Christopher R. Kennedy
Mary-Ellen Harper
Arne Holmgren
Julianna J. Tomlinson
Michael G. Schlossmacher
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Parkinson's Disease
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-022-01488-4

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Springer Medicine

Parkin coregulates glutathione metabolism in adult mammalian brain

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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