Oxidative Modifications of Parkin Underlie its Selective Neuroprotection in Adult Human Brain

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.

ELECTRONIC ANALOGY TO SIMULATE AND PREDICT THE DYNAMICS OF CELLULAR MECHANISM OF PARKINSON’S DISEASE STIMULATED BY ENVIRONMENTAL FACTORS

The present work aims to simulate and predict the molecular pathway of Parkinson’s disease (PD) initiated by environmental stress. It is designed to predict how protein aggregation and Lewy body (LB) formation leads to dopamine toxicity finally leading to cell death. The Mechanistic electronic modeling using Digital-Analog hybrid technique has been designed and implemented using MULTISIM 8.0 (National Instruments, USA) to simulate and predict the dynamics of PD pathway under environmental stress condition. The electronic network is initiated through an analog comparator circuit that compares the long-term environmental alterations with the cellular set point level of the molecular kinetics. The pattern of neuronal firing is simulated with the help of analog electronic circuit. The simulation results show a slow progressive rise in [Formula: see text]-synuclein/LB/dopamine toxicity level within the neuronal cells, which is comparable to published experimental and modeling studies associated with PD. Finally, cell death is demonstrated, which leads to neurodegeneration. In conclusion, our model allows a straightforward implementation of qualitative representation for systems where the network topology or pathway is at least moderately known.