title: Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease.
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.
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bayliss
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
authors.forename: Moyra B
authors.initials: MB
authors.lastname: Lemus
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
authors.forename: Romana
authors.initials: R
authors.lastname: Stark
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
authors.forename: Vanessa V
authors.initials: VV
authors.lastname: Santos
authors.affiliation: Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea SA28PP, United Kingdom.
authors.forename: Aiysha
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea SA28PP, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rees
authors.affiliation: St Vincent's Institute and Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia, and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Galic
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: John D
authors.initials: JD
authors.lastname: Elsworth
authors.affiliation: St Vincent's Institute and Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia, and.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea SA28PP, United Kingdom.
authors.forename: Jeffrey S
authors.identifier: http://orcid.org/0000-0002-4234-0033
authors.initials: JS
authors.lastname: Davies
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Victoria 3800, Australia, Zane.Andrews@monash.edu.
authors.forename: Zane B
authors.identifier: http://orcid.org/0000-0002-9097-7944
authors.initials: ZB
authors.lastname: Andrews
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D031204:Caloric Restriction; D002452:Cell Count; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D010300:Parkinson Disease / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D054439:Ghrelin; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D014446:Tyrosine 3-Monooxygenase; D055372:AMP-Activated Protein Kinases
keywords: AMPK; calorie restriction; ghrelin; stereology; substantia nigra