TY - JOUR
T1 - A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson's disease
T2 - Emerging concepts and challenges
AU - Vasquez, Velmarini
AU - Mitra, Joy
AU - Wang, Haibo
AU - Hegde, Pavana M.
AU - Rao, K. S.
AU - Hegde, Muralidhar L.
N1 - Funding Information:
Research in the Hegde Laboratory is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institute of Health (NIH) under the award number R01NS088645, the Muscular Dystrophy Association (MDA 294842), the ALS Association (15-IIP-204), and the Alzheimer's Association (NIRG-12-242135) awarded to M.L.H. and Melo Brain Funds (M.L.H. and K.S.R.). K.S.R. is supported by the National System of Investigation (SNI) grant of the National Secretariat of Science and Technology (SENACYT), Republic of Panama. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Funding Information:
Research in the Hegde Laboratory is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institute of Health (NIH) under the award number R01NS088645, the Muscular Dystrophy Association (MDA 294842 ), the ALS Association ( 15-IIP-204 ), and the Alzheimer’s Association (NIRG-12-242135) awarded to M.L.H. and Melo Brain Funds (M.L.H. and K.S.R.). K.S.R. is supported by the National System of Investigation (SNI) grant of the National Secretariat of Science and Technology ( SENACYT ), Republic of Panama. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Publisher Copyright:
© 2019 Elsevier Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - DNA damage
KW - Lewy bodies
KW - Mitochondrial dysfunction
KW - Parkinson's disease
KW - Protein misfolding/aggregation
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85077397501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077397501&partnerID=8YFLogxK
U2 - 10.1016/j.pneurobio.2019.101729
DO - 10.1016/j.pneurobio.2019.101729
M3 - Review article
C2 - 31863801
AN - SCOPUS:85077397501
VL - 185
JO - Progress in Neurobiology
JF - Progress in Neurobiology
SN - 0301-0082
M1 - 101729
ER -