Paper

Parkinson Disease-Linked Parkin Mediates Redox Reactions That Lower Oxidative Stress In Mammalian Brain

Nguyen, Angela P, Schlossmacher, Michael G, Pileggi, Chantal, Puente, Lawrence, Chan, Jennifer A, Shaw, Gary S, Sengupta, Rajib, Zecca, Luigi, Palmberg, Carina, Tomlinson, Julianna J, Jiang, Qiubo, Lavoie, Matthew J, Tokarew, Jacqueline M, Lengacher, Nathalie A, Callaghan, Steve, Boston, Heather, Park, David S, Ng, Andy C, Im, Doo Soon, Harper, Mary-Ellen, Fehr, Travis K, El Kodsi, Daniel N, Li, Juan, Takanashi, Masashi, Ratan, Rajiv R, Shutinoski, Bojan, Hattori, Nobutaka, Holmgren, Arne

2020

Overview

We recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. Nevertheless, this rise in oxidative stress led to changes in mitochondrial enzyme activities and the metabolism of glutathione in cells and mammalian brain. In parkin's absence reduced glutathione concentrations were increased including in human cortex. This compensation was not due to new glutathione synthesis but attributed to elevated oxidized glutathione (GSSG)-reductase activity. Moreover, we discovered that parkin also recycled GSSG to its reduced form. With this reaction, parkin became S-glutathionylated, e.g., at cysteines 59 and human-specific 95. This oxidative modification was reversed by glutaredoxin. Our results demonstrate that cytosolic parkin mediates anti-oxidant reactions including H2O2 reduction and glutathione regeneration. These reducing activities lead to a range of oxidative modifications in parkin itself. In parkin-deficient brain oxidative stress rises despite changes to maintain redox balance. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Cytosol / Glutaredoxin / Glutathione / Haploinsufficiency / Homeostasis / Hydrogen peroxide / Mitochondria / Movement disorders / MPTP / Neurodegenerative diseases / Neuroscience / Oxidants / Oxidation / Oxidative stress / Parkin protein / Parkinson's disease / Redox reactions / Reductase / Regeneration / Superoxide dismutase