1. Oxidative Modifications of Parkin Underlie its Selective Neuroprotection in Adult Human Brain
- Author
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Jacqueline M. Tokarew, Daniel N. El-Kodsi, Jennifer A. Chan, Clemens R. Scherzer, Gary S. Shaw, Ming Jin, Liqun Wang, An Tran, Andy C. H. Ng, Mei Zhang, Eve C. Tsai, Qiubo Jiang, Xiajun Dong, John Woulfe, Masashi Takanashi, Brian O'Nuallain, Juan Li, Travis K. Fehr, Peggy Taylor, Nathalie A. Lengacher, Jasmine M. Khan, Andrew B. West, Angela P. Nguyen, Nobutaka Hattori, Alexandre Prat, Julianna J. Tomlinson, Gergely Tóth, Kathryn R. Barber, Michael G. Schlossmacher, Arne Holmgren, Stephanie Zandee, Rajib Sengupta, and Lawrence G. Puente
- Subjects
0303 health sciences ,Chemistry ,Substantia nigra ,Human brain ,Oxidative phosphorylation ,Neuroprotection ,Parkin ,Cell biology ,nervous system diseases ,Midbrain ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Neuromelanin ,Dopamine ,medicine ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
SUMMARYThe 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.
- Published
- 2020
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