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Metabolites 2017, 7(2), 22; doi:10.3390/metabo7020022

Metabolic Investigations of the Molecular Mechanisms Associated with Parkinson’s Disease

1
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
2
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
3
Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
4
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
5
Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK
6
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece
*
Authors to whom correspondence should be addressed.
Academic Editors: Daniel Raftery, James Cox, Katja Dettmer and Adrian S. Culf
Received: 5 April 2017 / Revised: 16 May 2017 / Accepted: 16 May 2017 / Published: 24 May 2017
View Full-Text   |   Download PDF [6404 KB, uploaded 24 May 2017]   |  

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar cytoplasmic aggregates of α-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. View Full-Text
Keywords: Parkinson’s Disease; genetics; toxin synergy; molecular mechanisms; NMR; mass spectrometry Parkinson’s Disease; genetics; toxin synergy; molecular mechanisms; NMR; mass spectrometry
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Powers, R.; Lei, S.; Anandhan, A.; Marshall, D.D.; Worley, B.; Cerny, R.L.; Dodds, E.D.; Huang, Y.; Panayiotidis, M.I.; Pappa, A.; Franco, R. Metabolic Investigations of the Molecular Mechanisms Associated with Parkinson’s Disease. Metabolites 2017, 7, 22.

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