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

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Fig. 1. Biogenesis of miRNA and the release of miRNAs into the circulation by extracellular vesicles or as micro-vesicle free miRNAs. (40.76Kb)
Date
2020-02-01
Author
Vasquez, Velmarini
Mitra, Joy
Wang, Haibo
Hegde, Pavana M
Rao, KS Jagannatha
Hegde, Muralidhar L
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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.
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http://repositorio-indicasat.org.pa/handle/123456789/67
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El enlace del OAI de este repositorio: www.repositorio-indicasat.org.pa/oai/request
Repositorio del Instituto de Investigaciones Científicas y Servicios de Alta Tecnología de Panamá (INDICASAT).
Utiliza DSpace copyright © 2002-2016  DuraSpace
Contact Us | Send Feedback