Identification of an age-related Parkinson's disease risk factor that regulates sulfur metabolism

Human aging is the main risk factor for Parkinson’s disease (PD). To better understand age-related PD pathogenesis, we modeled PD with directly reprogrammed dopaminergic neurons (iDA) which preserve donor aging signatures. By transcriptome analysis and immunohistochemistry on postmortem tissues, we identified a sulfurtransferase, TSTD1, to be upregulated in aged and diseased individuals. TSTD1 catalyzes sulfur transfer from thiosulfate to glutathione (GSH). GSH and cysteine were significantly decreased in dopaminergic (DA) neurons with TSTD1 overexpression. Lower intracellular H2S levels and mitochondrial membrane potential (MMP) were identified in aged, PD iDA, and TSTD1 overexpressing embryonic stem cell (ES)-derived DA neurons. TSTD1 overexpression could lead to GAPDH inhibition and energy deficiency in neurons. We hypothesize that TSTD1 upregulation in aged and PD individuals could disrupt sulfur metabolism which compromises anti-oxidant capacity and energy production in neurons; both of these mechanisms have been implicated as triggers for DA neuronal degeneration in PD.