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

Robert Powers; Shulei Lei; Annadurai Anandhan; Darrell D Marshall; Bradley Worley; Ronald L Cerny; Eric D Dodds; Yuting Huang; Mihalis I Panayiotidis; Aglaia Pappa; Rodrigo Franco

doi:10.3390/metabo7020022

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

Metabolites. 2017 May 24;7(2):22. doi: 10.3390/metabo7020022.

Authors

Robert Powers^{1

2}, Shulei Lei³, Annadurai Anandhan^{4

5}, Darrell D Marshall⁶, Bradley Worley⁷, Ronald L Cerny⁸, Eric D Dodds⁹, Yuting Huang¹⁰, Mihalis I Panayiotidis¹¹, Aglaia Pappa¹², Rodrigo Franco^{13

14}

Affiliations

¹ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. rpowers3@unl.edu.
² Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. rpowers3@unl.edu.
³ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. shulei@huskers.unl.edu.
⁴ Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. ananbiochem@gmail.com.
⁵ School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. ananbiochem@gmail.com.
⁶ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. darrell.marshall@huskers.unl.edu.
⁷ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. bradley.worley@huskers.unl.edu.
⁸ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. rcerny1@unl.edu.
⁹ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. eric.dodds@unl.edu.
¹⁰ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. yuting.huang@huskers.unl.edu.
¹¹ Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK. m.panagiotidis@northumbria.ac.uk.
¹² Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece. apappa@mbg.duth.gr.
¹³ Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. rfrancocruz2@unl.edu.
¹⁴ School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. rfrancocruz2@unl.edu.

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.

Keywords: NMR; Parkinson’s Disease; genetics; mass spectrometry; molecular mechanisms; toxin synergy.

Publication types

Review

Grants and funding

P20 GM113126/GM/NIGMS NIH HHS/United States