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Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions

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Abstract

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.

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Acknowledgments

This work was supported by the National Institutes of Health Grants P20RR17675 Centers of Biomedical Research Excellence (COBRE), R01GM108975 (O.K.), the Scientist Development Grant of the American Heart Association (12SDG12090015, R.F.), and the Office of Research of the University of Nebraska-Lincoln. Part of this research was performed in facilities renovated with support from the NIH under Grant RR015468-01. We would like to thank the Flow Cytometry Core Facility at the Nebraska Center for Virology for the access to flow cytometry instrumentation (NIGMS grant number P30 GM103509).

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Authors and Affiliations

  1. Redox Biology Center, University of Nebraska-Lincoln, N200 Beadle Center, Lincoln, NE, 68588-0662, USA

    Annadurai Anandhan & Rodrigo Franco

  2. School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583-0905, USA

    Annadurai Anandhan & Rodrigo Franco

  3. Department of Chemistry, University of Nebraska-Lincoln, Hamilton Hall, Lincoln, NE, 68588-0304, USA

    Shulei Lei, Ronald L. Cerny & Robert Powers

  4. Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0662, USA

    Roman Levytskyy & Oleh Khalimonchuk

  5. Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus, Dragana, 68100, Alexandroupolis, Greece

    Aglaia Pappa

  6. School of Life Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, Scotland, UK

    Mihalis I. Panayiotidis

Authors
  1. Annadurai Anandhan
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  2. Shulei Lei
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  3. Roman Levytskyy
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  4. Aglaia Pappa
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  5. Mihalis I. Panayiotidis
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  6. Ronald L. Cerny
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  7. Oleh Khalimonchuk
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  8. Robert Powers
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  9. Rodrigo Franco
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Corresponding authors

Correspondence to Robert Powers or Rodrigo Franco.

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Anandhan, A., Lei, S., Levytskyy, R. et al. Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions. Mol Neurobiol 54, 3825–3842 (2017). https://doi.org/10.1007/s12035-016-9906-2

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  • DOI: https://doi.org/10.1007/s12035-016-9906-2

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