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Articles, Neurobiology of Disease

Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease

Jacqueline A. Bayliss, Moyra B. Lemus, Romana Stark, Vanessa V. Santos, Aiysha Thompson, Daniel J. Rees, Sandra Galic, John D. Elsworth, Bruce E. Kemp, Jeffrey S. Davies and Zane B. Andrews
Journal of Neuroscience 9 March 2016, 36 (10) 3049-3063; https://doi.org/10.1523/JNEUROSCI.4373-15.2016
Jacqueline A. Bayliss
1Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia,
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Moyra B. Lemus
1Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia,
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Romana Stark
1Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia,
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Vanessa V. Santos
1Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia,
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Aiysha Thompson
2Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea SA28PP, United Kingdom,
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Daniel J. Rees
2Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea SA28PP, United Kingdom,
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Sandra Galic
3St Vincent's Institute and Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia, and
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John D. Elsworth
4Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520
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Bruce E. Kemp
3St Vincent's Institute and Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia, and
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Jeffrey S. Davies
2Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea SA28PP, United Kingdom,
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Zane B. Andrews
1Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia,
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Abstract

Calorie restriction (CR) is neuroprotective in Parkinson's disease (PD) although the mechanisms are unknown. In this study we hypothesized that elevated ghrelin, a gut hormone with neuroprotective properties, during CR prevents neurodegeneration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. CR attenuated the MPTP-induced loss of substantia nigra (SN) dopamine neurons and striatal dopamine turnover in ghrelin WT but not KO mice, demonstrating that ghrelin mediates CR's neuroprotective effect. CR elevated phosphorylated AMPK and ACC levels in the striatum of WT but not KO mice suggesting that AMPK is a target for ghrelin-induced neuroprotection. Indeed, exogenous ghrelin significantly increased pAMPK in the SN. Genetic deletion of AMPKβ1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects. We consider targeting AMPK in dopamine neurons may recapitulate neuroprotective effects of CR without requiring dietary intervention.

SIGNIFICANCE STATEMENT The neuroprotective mechanisms of calorie restriction (CR) in Parkinson's disease are unknown. Indeed, the difficulty to adhere to CR necessitates an alternative method to recapitulate the neuroprotective benefits of CR while bypassing dietary constraints. Here we show that CR increases plasma ghrelin, which targets substantia nigra dopamine to maintain neuronal survival. Selective deletion on AMPK beta1 and beta2 subunits only in DAT cre-expressing neurons shows that the ghrelin-induced neuroprotection requires activation of AMPK in substantia nigra dopamine neurons. We have discovered ghrelin as a key metabolic signal, and AMPK in dopamine neurons as its target, which links calorie restriction with neuroprotection in Parkinson's disease. Thus, targeting AMPK in dopamine neurons may provide novel neuroprotective benefits in Parkinson's disease.

  • AMPK
  • calorie restriction
  • ghrelin
  • stereology
  • substantia nigra
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The Journal of Neuroscience: 36 (10)
Journal of Neuroscience
Vol. 36, Issue 10
9 Mar 2016
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Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease
Jacqueline A. Bayliss, Moyra B. Lemus, Romana Stark, Vanessa V. Santos, Aiysha Thompson, Daniel J. Rees, Sandra Galic, John D. Elsworth, Bruce E. Kemp, Jeffrey S. Davies, Zane B. Andrews
Journal of Neuroscience 9 March 2016, 36 (10) 3049-3063; DOI: 10.1523/JNEUROSCI.4373-15.2016

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Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease
Jacqueline A. Bayliss, Moyra B. Lemus, Romana Stark, Vanessa V. Santos, Aiysha Thompson, Daniel J. Rees, Sandra Galic, John D. Elsworth, Bruce E. Kemp, Jeffrey S. Davies, Zane B. Andrews
Journal of Neuroscience 9 March 2016, 36 (10) 3049-3063; DOI: 10.1523/JNEUROSCI.4373-15.2016
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Keywords

  • AMPK
  • calorie restriction
  • ghrelin
  • stereology
  • substantia nigra

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