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

Authors

Robert Powers, University of Nebraska - LincolnFollow
Shulei Lei, University of Nebraska-LincolnFollow
Annadurai Anandhan, University of Nebraska-LincolnFollow
Darrell D. Marshall, University of Nebraska-LincolnFollow
Bradley Worley, University of Nebraska-LincolnFollow
Ronald Cerny, University of Nebraska-LincolnFollow
Eric D. Dodds, University of Nebraska-LincolnFollow
Yuting Huang, University of Nebraska - Lincoln
Mihalis I. Panayiotidis, Northumbria University, Newcastle Upon TyneFollow
Aglaia Pappa, Democritus University of ThraceFollow
Rodrigo Franco, University of Nebraska-LincolnFollow

Date of this Version

2017

Citation

Metabolites 2017, 7, 22; doi:10.3390/metabo7020022

Comments

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license

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.