title: 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 that GSH depletion in these cells was due to ATP loss associated with mitochondrial dysfunction. ATP depletion elicited by combined A53T expression and proteasome inhibition results in decreased de novo synthesis of GSH via the rate-limiting enzyme gamma-glutamyl cysteine ligase. Based on these data and other recent reports, we propose a novel dynamic model to explain how the presence of mutated alpha-syn protein or proteasome inhibition may individually impact on mitochondrial function and in combination result in alterations in GSH metabolism via enhanced mitochondrial dysfunction.
authors.affiliation: Cell Works Group, Inc., 3rd Floor, West Wing, Neil-Rao Tower, 118, Road 3, EPIP, White Field, Bangalore 560066, India.
authors.forename: Shireen
authors.initials: S
authors.lastname: Vali
authors.forename: Shankar J
authors.initials: SJ
authors.lastname: Chinta
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.forename: Zeba
authors.initials: Z
authors.lastname: Sultana
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.forename: Purushottam
authors.initials: P
authors.lastname: Sharma
authors.forename: S
authors.initials: S
authors.lastname: Sharada
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
authors.forename: M M Srinivas
authors.initials: MM
authors.lastname: Bharath