Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392175v1?rss=1 Authors: Tokarew, J. M., El Kodsi, D. N., Lengacher, N. A., Fehr, T. K., Nguyen, A. P., Shutinoski, B., O'Nuallain, B., Jin, M., Khan, J., Ng, A. C. H., Li, J., Jiang, Q., Zhang, M., Wang, L., Sengupta, R., Barber, K., Tran, A., Zandee, S., Dong, X., Scherzer, C. R., Prat, A., Tsai, E., Takanashi, M., Hattori, N., Chan, J. A., Zecca, L., West, A., Holmgren, A., Puente, L., Shaw, G. S., Toth, G., Woulfe, J., Taylor, P., Tomlinson, J. J., Schlossmacher, M. G. Abstract: The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions, which are reflected in its posttranslational modifications. We found that in human control brain, including the S. nigra, parkin is largely insoluble after age 40 years, which is linked to its oxidation, e.g., at Cys95 and Cys253. In mice, oxidative stress increases posttranslational modifications at parkin cysteines and reduces its solubility. Oxidation of recombinant parkin also promotes insolubility and aggregate formation, but in parallel, lowers hydrogen peroxide (H2O2). This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. Intriguingly, in parkin-deficient human brain H2O2 concentrations are elevated. In prkn-null mice, H2O2 levels are dysregulated under oxidative stress conditions, such as acutely by MPTP-toxin exposure or chronically due to a second genetic hit. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic M17 cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at primate-specific Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation. In sections of normal, adult human midbrain, parkin specifically co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration. Copy rights belong to original authors. Visit the link for more info