RT Journal Article
SR Electronic
T1 Oxidative Modifications of Parkin Underlie its Selective Neuroprotection in Adult Human Brain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.19.953034
DO 10.1101/2020.02.19.953034
A1 Jacqueline M. Tokarew
A1 Daniel N. El-Kodsi
A1 Nathalie A. Lengacher
A1 Travis K. Fehr
A1 Angela P. Nguyen
A1 Brian O’Nuallain
A1 Ming Jin
A1 Jasmine M. Khan
A1 Andy C. H. Ng
A1 Juan Li
A1 Qiubo Jiang
A1 Mei Zhang
A1 Liqun Wang
A1 Rajib Sengupta
A1 Kathryn R. Barber
A1 An Tran
A1 Stephanie Zandee
A1 Xiajun Dong
A1 Clemens R. Scherzer
A1 Alexandre Prat
A1 Eve Tsai
A1 Masashi Takanashi
A1 Nobutaka Hattori
A1 Jennifer A. Chan
A1 Andrew B. West
A1 Arne Holmgren
A1 Lawrence Puente
A1 Gary S. Shaw
A1 Gergely Toth
A1 John M. Woulfe
A1 Peggy Taylor
A1 Julianna J. Tomlinson
A1 Michael G. Schlossmacher
YR 2020
UL http://biorxiv.org/content/early/2020/02/20/2020.02.19.953034.abstract
AB The mechanisms by which Parkinson disease-linked parkin confers neuroprotection of human dopamine cells remain elusive. We hypothesized that its cysteines mediate multiple anti-oxidant effects in the midbrain. By studying >60 control specimens, we found that in adult human brain - but not in skeletal muscle- parkin is mostly aggregated and insoluble due to oxidative modifications, such as at C253. In vitro, parkin’s oxidation directly reduces hydrogen peroxide (H2O2) to water. In parkin-deficient human brain, H2O2 concentrations are elevated. In dopamine toxicity studies, wild-type parkin -but not disease-associated mutants-prevents neural death by lowering H2O2 and sequestering radicals within insoluble aggregates. Parkin conjugates dopamine metabolites at the human-specific residue C95 and augments melanin formation in vitro. Using epitope-mapped antibodies, we found that in adult Substantia nigra neurons parkin localizes to neuromelanin within LAMP-3/CD63-positive lysosomes. We conclude that parkin’s own oxidation, previously considered a loss-of-function event, underlies three neuroprotective effects in adult midbrain: its cysteines participate in H2O2 reduction, dopamine radical conjugation and the formation of neuromelanin.