Insights into the effects of alpha-synuclein expression and proteasome inhibition on glutathione metabolism through a dynamic in silico model of Parkinson's disease: validation by cell culture data.

ABSTRACT: Dopaminergic neurodegeneration during Parkinson disease (PD) involves several pathways including proteasome inhibition, alpha-synuclein (alpha-syn) aggregation, mitochondrial dysfunction, and glutathione (GSH) depletion. We have utilized a systems biology approach and built a dynamic model to understand and link the various events related to PD pathophysiology. We have corroborated the modeling data by examining the effects of alpha-syn expression in the absence and presence of proteasome inhibition on GSH metabolism in dopaminergic neuronal cultures. We report here that the expression of the mutant A53T form of alpha-syn is neurotoxic and causes GSH depletion in cells after proteasome inhibition, compared to wild-type alpha-syn-expressing cells and vector control. Modeling data predicted

SUBMITTER: Vali S 

PROVIDER: S-EPMC2744580 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature