Metabolic Investigations of Molecular Mechanisms Associated with Parkinson’s Disease.
Year: 2016
Type: conference-abstract
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar cytoplasmic aggregates of α-synuclein (i.e., Lewy bodies [LB]) and the associated loss of dopaminergic cells in the substantia nigra. But, mutations in genes such as α-synuclein (SNCA) account for only 10% of PD occurrences. The exposure to environmental toxicants including pesticides (e.g. paraquat [PQ]) and manganese (Mn), are also recognized as important PD risk factors. 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 report a toxic synergistic effect between α-synuclein and either paraquat or Mn treatment. We identified an essential role for central carbon (glucose) metabolism in dopaminergic cell death induced by paraquat or Mn 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 AMPK activation. The overexpression of α-synuclein further stimulated an increase in glucose uptake and AMPK activity, but impaired glucose metabolism. In effect, α-synuclein activity directs additional carbon to the PPP to supply paraquat redox cycling. Alternatively, Mn induces an upregulation in glycolysis and the malate-aspartate shuttle to compensate for energy depletion due to Mn toxicity. Mn treatment causes a decrease in carbon flow through the TCA cycle and a disruption in pyruvate metabolism, which are consistent with a dysfunctional mitochondria and inhibition of pyruvate dehydrogenase. The overexpression of α-synuclein was shown to potentiate Mn toxicity by glycolysis impairment by inhibiting aldolase activity. In effect, α-synuclein overexpression negates the metabolic response to alleviate Mn toxicity that results in an increase in cell death.
DOI: 10.3390/iecm-1-a006
Authors: Robert Powers, Shulei Lei, Annadurai Anandhan, Ronald Cerny, Eric Dodds, Aracely Garcia-Garcia, Reilly Grealish, Yuting Huang, Oleh Khalimonchuk, Roman Levytskyy, Jiahui Li, Nandakumar Madayiputhiya, Renu Nandakumar, Mihalis Panayiotidis, Aglaia Pappa, Robert Stanton, Laura Zavala-Flores, Rodrigo Franco
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W2547807340