Glutathione Deficiency in Gclm Null Mice Results in Complex I Inhibition and Dopamine Depletion following Paraquat Administration.

Depletion of glutathione has been shown to occur in autopsied brains of patients with Parkinson's disease (PD) as well as in animal models of PD. The goal of this study was to determine if chronic GSH deficiency per se resulted in complex I inhibition and/or dopamine depletion and whether these indices were further potentiated by aging or administration of paraquat, a redox-cycling herbicide that produces a PD-like neurodegeneration model in rodents (Brooks et al. 1999; McCormack et al. 2002). Deletion of the rate-limiting GSH synthesis gene, glutamate-cysteine ligase modifier subunit (Gclm) leads to significantly lower GSH concentrations in all tissues including brain. Gclm null (Gclm-/-) mice provide a model of prolonged GSH depletion to explore the relationship between GSH, complex I inhibition and dopamine loss in vivo. Despite ~60% depletion of brain GSH in Gclm-/- mice of ages 3-5 or 14-16 months, striatal complex I activity, dopamine levels, 3-nitrotyroine/tyrosine ratios, aconitase activity and CoASH remained unchanged. Administration of paraquat (10 mg/kg, twice/week, 3 weeks) to 3-5 month old Gclm-/- mice resulted in significantly decreased aconitase activity, complex I activity and dopamine levels but not in 3-5 month old Gclm+/+ mice. Furthermore, paraquat-induced inhibition of complex I and aconitase activities in Gclm-/- mice was observed in the striatum but not cortex. The results suggest that chronic deficiency of GSH in Gclm-/- mice was not sufficient to result in complex I inhibition or dopamine depletion perhaps due to homeostatic mechanisms but required an additional oxidative stress insult as shown with paraquat exposure.

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