ABSTRACT Both α-synuclein expression and neuronal glutathione levels are recognized as crucial factors in the pathogenesis of Parkinson’s disease (PD), but how these factors interact is poorly understood. This knowledge gap is of therapeutic relevance, because pharmacological agents for restoring neuronal glutathione levels are clinically available. In PD, the accumulation of α-synuclein oligomers or higher-order aggregates is associated with oxidative stress, glutathione depletion, and neuronal death. Additionally, the clearance of α-synuclein is impaired by the tyrosine kinase c-Abl, which is activated by oxidative stress. Glutathione is the dominant thiol redox species and is used by cells to both scavenge reactive oxygen species and repair oxidatively damage proteins. Here we aim to identify specific cause-effect relationships between neuronal thiol redox status, c-Abl activation, and α-synuclein - mediated pathology. Our underlying hypothesis is that α- synuclein aggregates drive reactive oxygen species formation through metal-catalyzed processes, and the resulting glutathione depletion contributes to α-synuclein aggregation in a feed-forward manner. The studies will use cell culture models in which both α- synuclein expression and thiol redox state can be controlled and monitored. The studies will also use a novel double-transgenic mouse generated by crossing the Thy-1 α-synuclein “Line 61” mouse, which exhibits α-synuclein aggregate formation, with the EAAT3-/- mouse, which exhibits low neuronal glutathione levels. The glutathione defect in these mice can be reversed with oral cysteine pro-drugs. This permits both experimental manipulation of neuronal thiol redox state in situ, and an assessment of potential disease -modifying therapeutic agents for PD. 1