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selective inhibition of mitochondrial complex I activity: implications for
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Glutathione Articles - Parkinson's Disease
Glutathione Depletion in PC12 Results in Selective Inhibition of
Mitochondrial Complex I Activity: Implications for Parkinson’s Disease
Nandita JHA, Octavian Jurma, Giovanna Lalli, Yi Liu, Edward Harvey Pettus,
John Timothy Greenamyre, Prui-Ming Liu
The Journal of Biological Chemistry. 2000 Aug; Vol 275(34):26096-101.
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SUMMARY
Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson’s disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. We have generated dopaminergic PC12 cell lines in which levels of GSH can be inducibly downregulated via doxycycline (dox) induction of antisense messages against both the heavy and light subunits of gamma glutamyl cysteine synthetase (gGCS), the ratelimiting enzyme in glutathione synthesis. Downregulation of GCS results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSHdepleted PC12 cells appears to be due to a selective inhibition of complex I activity as a result of thiol oxidation. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction which ultimately leads to dopaminergic cell death associated with PD.
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