TY - JOUR
T1 - Metabolic investigations of the molecular mechanisms associated with Parkinson’s disease
AU - Powers, Robert
AU - Lei, Shulei
AU - Anandhan, Annadurai
AU - Marshall, Darrell D.
AU - Worley, Bradley
AU - Cerny, Ronald L.
AU - Dodds, Eric D.
AU - Huang, Yuting
AU - Panayiotidis, Mihalis I.
AU - Pappa, Aglaia
AU - Franco, Rodrigo
N1 - Funding Information:
This work was supported by the National Institutes of Health Grants P20RR17675, R01AI087668, R21AI087561, and R01CA163649, Centers of Biomedical Research Excellence (COBRE), P30 GM103335 and P20GM113126, the Scientist Development Grant of the American Heart Association (12SDG12090015), the Nebraska Tobacco Settlement Biomedical Research Development Fund, the Nebraska Center for Integrated Biomolecular Communication Systems Biology Core (NIH National Institutes of General Medical Sciences P20-GM113126), and the Office of Research of the University of Nebraska-Lincoln. Part of this research was performed in facilities renovated with support from the NIH under Grant RR015468. We would like to thank the Flow Cytometry Core Facility at the Nebraska Center for Virology for the access to flow cytometry instrumentation (NIGMS grant number P30 GM103509).
Publisher Copyright:
© 2017 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2017/6
Y1 - 2017/6
N2 - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar cytoplasmic aggregates of αα-synuclein (i.e., Lewy bodies) and the associated loss of dopaminergic cells in the substantia nigra. Mutations in genes such as α-synuclein (SNCA) account for only 10% of PD occurrences. Exposure to environmental toxicants including pesticides and metals (e.g., paraquat (PQ) and manganese (Mn)) is also recognized as an important PD risk factor. Thus, aging, genetic alterations, and environmental factors all contribute to the etiology of PD. In fact, both genetic and environmental factors are thought to interact in the promotion of idiopathic PD, but the mechanisms involved are still unclear. In this study, we summarize our findings to date regarding the toxic synergistic effect between α-synuclein and paraquat treatment. We identified an essential role for central carbon (glucose) metabolism in dopaminergic cell death induced by paraquat treatment that is enhanced by the overexpression of α-synuclein. PQ “hijacks” the pentose phosphate pathway (PPP) to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. PQ also stimulated an increase in glucose uptake, the translocation of glucose transporters to the plasma membrane, and AMP-activated protein kinase (AMPK) activation. The overexpression of α-synuclein further stimulated an increase in glucose uptake and AMPK activity, but impaired glucose metabolism, likely directing additional carbon to the PPP to supply paraquat redox cycling.
AB - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar cytoplasmic aggregates of αα-synuclein (i.e., Lewy bodies) and the associated loss of dopaminergic cells in the substantia nigra. Mutations in genes such as α-synuclein (SNCA) account for only 10% of PD occurrences. Exposure to environmental toxicants including pesticides and metals (e.g., paraquat (PQ) and manganese (Mn)) is also recognized as an important PD risk factor. Thus, aging, genetic alterations, and environmental factors all contribute to the etiology of PD. In fact, both genetic and environmental factors are thought to interact in the promotion of idiopathic PD, but the mechanisms involved are still unclear. In this study, we summarize our findings to date regarding the toxic synergistic effect between α-synuclein and paraquat treatment. We identified an essential role for central carbon (glucose) metabolism in dopaminergic cell death induced by paraquat treatment that is enhanced by the overexpression of α-synuclein. PQ “hijacks” the pentose phosphate pathway (PPP) to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. PQ also stimulated an increase in glucose uptake, the translocation of glucose transporters to the plasma membrane, and AMP-activated protein kinase (AMPK) activation. The overexpression of α-synuclein further stimulated an increase in glucose uptake and AMPK activity, but impaired glucose metabolism, likely directing additional carbon to the PPP to supply paraquat redox cycling.
KW - Genetics
KW - Mass spectrometry
KW - Molecular mechanisms
KW - NMR
KW - Parkinson’s disease
KW - Toxin synergy
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U2 - 10.3390/metabo7020022
DO - 10.3390/metabo7020022
M3 - Review article
C2 - 28538683
AN - SCOPUS:85020936171
VL - 7
JO - Metabolites
JF - Metabolites
SN - 2218-1989
IS - 2
M1 - 22
ER -