A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson's disease: Emerging concepts and challenges. (February 2020)

• Record Type: Journal Article
• Authors: Vasquez, Velmarini; Mitra, Joy; Wang, Haibo; Hegde, Pavana M.; Rao, K.S.; Hegde, Muralidhar L.
• Is Part Of: Progress in neurobiology. Volume 185(2020)
• Publication Date: 2020-02
• Subjects: α-synuclein -- Parkinson's disease -- Lewy bodies -- DNA damage -- Mitochondrial dysfunction -- Protein misfolding/aggregation; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2019.101729
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: This review outlines the complex and multi-faceted neurotoxic role of α-synuclein in Parkinson's disease. A particular emphasis is given to the emerging role of α-synuclein in promoting genome instability. Pro-oxidant metal ions, together with reactive oxygen species, contributes to α- synuclein's DNA binding and genotoxicity. Chromatin-bound oxidized α-synuclein causes strand breaks in genome. Identification of potential residues mediating α-synuclein-DNA binding by Protein-DNA docking. Abstract: α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) present 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 role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.