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

Research output: Contribution to journalReview articlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number22
JournalMetabolites
Volume7
Issue number2
DOIs
StatePublished - Jun 2017

Keywords

  • Genetics
  • Mass spectrometry
  • Molecular mechanisms
  • NMR
  • Parkinson’s disease
  • Toxin synergy

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'Metabolic investigations of the molecular mechanisms associated with Parkinson’s disease'. Together they form a unique fingerprint.

Cite this