Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions
| Autor: | Oleh Khalimonchuk, Annadurai Anandhan, Mihalis I. Panayiotidis, Rodrigo Franco, Roman M. Levytskyy, Robert Powers, Aglaia Pappa, Ronald L. Cerny, Shulei Lei |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Paraquat Programmed cell death Glucose uptake Neuroscience (miscellaneous) Glucose Transport Proteins Facilitative Nitric Oxide Synthase Type II B100 B200 Article Cell Line Pentose Phosphate Pathway 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Dopaminergic Cell Autophagy Animals Mice Knockout biology Cell Death Dopaminergic Neurons Adenylate Kinase C100 Glucose transporter AMPK Brain Biological Transport A100 C700 C900 Cell biology Rats Enzyme Activation Mice Inbred C57BL B900 030104 developmental biology Glucose Neurology Autophagy Protein 5 biology.protein Metabolome alpha-Synuclein Gene-Environment Interaction 030217 neurology & neurosurgery GLUT4 Signal Transduction |
| ISSN: | 0893-7648 |
| Popis: | While environmental exposures are not the single cause of Parkinson’s disease (PD), their interaction with genetic alterations is thought to contribute to neuronal dopaminergic degeneration. However, the mechanisms involved in dopaminergic cell death induced by gene-environment interactions remain unclear. In this work, we have revealed for the first time the role of central carbon metabolism and metabolic dysfunction in dopaminergic cell death induced by paraquat (PQ)-α-synuclein interaction. The toxicity of PQ in dopaminergic N27 cells was significantly reduced by glucose deprivation, inhibition of hexokinase with 2-deoxy-D-glucose (2-DG), or equimolar substitution of glucose with galactose, which evidenced the contribution of glucose metabolism to PQ-induced cell death. PQ also stimulated an increase in glucose uptake, and the translocation of glucose transporter type 4 (GLUT4) and Na+-glucose transporters isoform 1 (SGLT1) proteins to the plasma membrane, but only inhibition of GLUT-like transport with STF-31 or ascorbic acid reduced PQ-induced cell death. Importantly, while autophagy protein 5 (ATG5)/unc-51 like autophagy activating kinase 1 (ULK1)-dependent autophagy protected against PQ toxicity, the inhibitory effect of glucose deprivation on cell death progression was largely independent of autophagy or mammalian target of rapamycin (mTOR) signaling. PQ selectively induced metabolomic alterations and adenosine monophosphate-activated protein kinase (AMPK) activation in the midbrain and striatum of mice chronically treated with PQ. Inhibition of AMPK signaling led to metabolic dysfunction and an enhanced sensitivity of dopaminergic cells to PQ. In addition, activation of AMPK by PQ was prevented by inhibition of the inducible nitric oxide syntase (iNOS) with 1400W, but PQ had no effect on iNOS levels. Overexpression of wild type or A53T mutant α-synuclein stimulated glucose uptake and PQ toxicity, and this toxic synergism was reduced by inhibition of glucose metabolism/transport and the pentose phosphate pathway (6-aminonicotinamide). These results demonstrate that glucose metabolism and AMPK regulate dopaminergic cell death induced by gene (α-synuclein)-environment (PQ) interactions. |
| Databáze: | OpenAIRE |
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