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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01NS065013"],"award-info":[{"award-number":["R01NS065013"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Uttra and Sam Bhargava Family"},{"name":"Department of Medicine at The Ottawa Hospital and Faculty of Medicine"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We recently discovered that the expression of <jats:italic>PRKN<\/jats:italic>, 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 <jats:italic>prkn<\/jats:italic> with <jats:italic>Sod2<\/jats:italic> haploinsufficiency in mice. Although adult <jats:italic>prkn<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>\/\/<jats:italic>Sod2<\/jats:italic><jats:sup>\u00b1<\/jats:sup> animals did not develop dopamine cell loss in the <jats:italic>S. nigra<\/jats:italic>, 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 <jats:italic>PRKN<\/jats:italic> expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, <jats:italic>PRKN-<\/jats:italic>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 <jats:italic>S<\/jats:italic>-glutathionylated by the other (GSSG\u2009+\u2009P-SH <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\to$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mo>\u2192<\/mml:mo>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> GSH\u2009+\u2009P-<jats:italic>S<\/jats:italic>-SG), including at cysteines 59, 95 and 377. Moreover, parkin\u2019s <jats:italic>S<\/jats:italic>-glutathionylation was reversible by glutaredoxin activity. In summary, we found that <jats:italic>PRKN<\/jats:italic> gene expression contributes to the network of available thiols in the cell, including by parkin\u2019s participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin\u2019s 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.<\/jats:p>","DOI":"10.1186\/s40478-022-01488-4","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T06:02:58Z","timestamp":1674453778000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Parkin coregulates glutathione metabolism in adult mammalian brain"],"prefix":"10.1186","volume":"11","author":[{"given":"Daniel N.","family":"El Kodsi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Tokarew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajib","family":"Sengupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie A.","family":"Lengacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajanta","family":"Chatterji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela P.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Boston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiubo","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Palmberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Pileggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chet E.","family":"Holterman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojan","family":"Shutinoski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis K.","family":"Fehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"LaVoie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv R.","family":"Ratan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary S.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Takanashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutaka","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary-Ellen","family":"Harper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Holmgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianna J.","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0394-0300","authenticated-orcid":false,"given":"Michael G.","family":"Schlossmacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"1488_CR1","doi-asserted-by":"publisher","first-page":"e0176363","DOI":"10.1371\/journal.pone.0176363","volume":"12","author":"L Abela","year":"2017","unstructured":"Abela L, Spiegel R, Crowther LM, Klein A, Steindl K, Papuc SM, Joset P, Zehavi Y, Rauch A, Plecko B, Simmons TL (2017) Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency. 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Dr. M. Schlossmacher received travel reimbursements from the Michael J. Fox Foundation for Parkinson\u2019s Research for participation in industry summits and consulting fees (Biogen; Neuramedy; Samsara) as well as royalties from Eli Lilly for patents unrelated to this work. Dr. A. Holmgren (deceased) served as chairman and senior scientist at IMCO Corporation Ltd AB, Stockholm, Sweden. No additional, potentially competing financial interests are declared.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19"}}