Mostrar el registro sencillo del ítem

dc.contributor.authorVasquez, Velmarini
dc.contributor.authorMitra, Joy
dc.contributor.authorWang, Haibo
dc.contributor.authorHegde, Pavana M
dc.contributor.authorRao, KS Jagannatha
dc.contributor.authorHegde, Muralidhar L
dc.date.accessioned2020-06-16T00:02:03Z
dc.date.available2020-06-16T00:02:03Z
dc.date.issued2020-02-01
dc.identifier.otherhttps://doi.org/10.1016/j.pneurobio.2019.101729
dc.identifier.urihttp://repositorio-indicasat.org.pa/handle/123456789/67
dc.descriptionα-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.en_US
dc.description.abstractα-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.en_US
dc.language.isoenen_US
dc.subjectα-synucleinen_US
dc.subjectParkinson’s diseaseen_US
dc.subjectLewy bodiesen_US
dc.subjectDNA damageen_US
dc.subjectMitochondrial dysfunctionen_US
dc.subjectProtein misfolding/aggregationen_US
dc.titleA multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson’s disease: Emerging concepts and challengesen_US
dc.typeArticleen_US


Ficheros en el ítem

Thumbnail

Este ítem aparece en la(s) siguiente(s) colección(ones)

Mostrar el registro sencillo del ítem