402 - Thiol Oxidation Mediated Redox Signaling Triggers Specific Dopaminergic Neurodegeneration in Parkinson′s Disease

Abstract

Oxidative stress has been implicated in pathogenesis of Parkinson’s disease (PD), but it is yet unclear as to how the generalized ROS generation leads to degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Activation of redox driven signaling pathways may contribute to the specific cell death seen in PD. Using the MPTP mouse model of PD, we have established that stress-regulated MAPK signaling, specifically p38 MAPK-dependent death signaling, is selectively activated in dopaminergic neurons, while JNK is activated in microglia. Further, we found ASK1 as an upstream MAP3K responsible for p38 activation. ASK1, in turn, was selectively activated by TNF upregulation acting through thiol oxidation of Trx1, a negative regulator of ASK1 activity. Further, we also observed inhibition of Akt-mediated cell survival pathway through cysteine oxidation in Akt. As protein thiol oxidation emerged as a major contributor towards selective cell death signaling, we developed a novel diamide-induced mouse model of PD to examine whether thiol oxidation alone, caused by diamide, could trigger PD-relevant phenotype. Stereotaxic injection of diamide into mouse brain led to extensive dopaminergic neurodegeneration, coupled with biochemical and behavioral deficits as observed in PD, and activation of ASK1-mediated cell death signaling. α-Synuclein aggregation, not often seen in other models of PD, was also reproduced in this model. Current studies are underway to investigate whether Grx1 inhibition in vivo (leading to increased glutathionylation and protein thiol oxidation), results in PD pathology. Overall, these studies demonstrate the critical role of thiol oxidation in triggering neurodegeneration in PD.