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Ghrelin-AMPK signaling mediates the neuroprotective effects of calorie restriction in Parkinson's Disease
Bayliss, Jacqueline A. Lemus, Moyra B. Stark, Romana Santos, Vanessa V. Thompson, Aiysha Rees, Daniel J. Galic, Sandra Elsworth, John D. Kemp, Bruce Ernest Davies, Jeffrey S.
Bayliss, Jacqueline A.
Lemus, Moyra B.
Stark, Romana
Santos, Vanessa V.
Thompson, Aiysha
Rees, Daniel J.
Galic, Sandra
Elsworth, John D.
Kemp, Bruce Ernest
Davies, Jeffrey S.
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.
Keywords
ampk calorie restriction, ghrelin, stereology, substantia nigra
Date
2016
Type
Journal article
Journal
Journal of Neuroscience
Book
Volume
36
Issue
10
Page Range
3049-3063
Article Number
ACU Department
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Open access
License
File Access
Open