Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions.
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 the 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 in the levels of glucose transporter type 4 (GLUT4) and Na+-glucose transporters isoform 1 (SGLT1) proteins, 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 accumulation 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.
Redox Biology Center, University of Nebraska-Lincoln, N200 Beadle Center, Lincoln, NE, 68588-0662, USA.|School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583-0905, USA.
Annadurai
A
Anandhan
Department of Chemistry, University of Nebraska-Lincoln, Hamilton Hall, Lincoln, NE, 68588-0304, USA.
Shulei
S
Lei
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0662, USA.
Roman
R
Levytskyy
Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus, Dragana, 68100, Alexandroupolis, Greece.
Aglaia
A
Pappa
School of Life Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, Scotland, UK.
Mihalis I
MI
Panayiotidis
Department of Chemistry, University of Nebraska-Lincoln, Hamilton Hall, Lincoln, NE, 68588-0304, USA.
Ronald L
RL
Cerny
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0662, USA.
Oleh
O
Khalimonchuk
Department of Chemistry, University of Nebraska-Lincoln, Hamilton Hall, Lincoln, NE, 68588-0304, USA. rpowers3@unl.edu.
Robert
R
Powers
Redox Biology Center, University of Nebraska-Lincoln, N200 Beadle Center, Lincoln, NE, 68588-0662, USA. rfrancocruz2@unl.edu.|School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583-0905, USA. rfrancocruz2@unl.edu.
Rodrigo
R
Franco
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D059647:Gene-Environment Interaction; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity*; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051844:alpha-Synuclein / Q000633:toxicity*
D051246:Glucose Transport Proteins, Facilitative; D051844:alpha-Synuclein; D052247:Nitric Oxide Synthase Type II; D000263:Adenylate Kinase; D005947:Glucose; D010269:Paraquat
Adenosine monophosphate-activated kinase; Autophagy; Glucose transporters; Glycolysis; Metabolomics; Parkinson’s disease; Pesticides; α-Synuclein