A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson’s disease: Emerging concepts and challenges

Publication date: Available online 18 December 2019Source: Progress in NeurobiologyAuthor(s): Velmarini Vasquez, Joy Mitra, Haibo Wang, Pavana M. Hegde, K.S. Rao, Muralidhar L. HegdeAbstractα-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) that are found in dopaminergic neurons affected by Parkinson’s disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a “double whammy” in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein’s DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction, warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic r...
Source: Progress in Neurobiology - Category: Neuroscience Source Type: research