title: Acylated but not des-acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease.
abstract: The gut hormone ghrelin is widely beneficial in many disease states. However, ghrelin exists in two distinctive isoforms, each with its own metabolic profile. In Parkinson's Disease (PD) acylated ghrelin administration is neuroprotective, however, the role of des-acylated ghrelin remains unknown. In this study, we wanted to identify the relative contribution each isoform plays using the MPTP model of PD. Chronic administration of acylated ghrelin in mice lacking both isoforms of ghrelin (Ghrelin KO) attenuated the MPTP-induced loss on tyrosine hydroxylase (TH) neuronal number and volume and TH protein expression in the nigrostriatal pathway. Moreover, acylated ghrelin reduced the increase in glial fibrillary acidic protein and Ionized calcium binding adaptor molecule 1 microglia in the substantia nigra. However, injection of acylated ghrelin also elevated plasma des-acylated ghrelin, indicating in vivo deacetylation. Next, we chronically administered des-acylated ghrelin to Ghrelin KO mice and observed no neuroprotective effects in terms of TH cell number, TH protein expression, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 cell number. The lack of a protective effect was mirrored in ghrelin-O-acyltransferase KO mice, which lack the ability to acylate ghrelin and consequently these mice have chronically increased plasma des-acyl ghrelin. Plasma corticosterone was elevated in ghrelin-O-acyltransferase KO mice and with des-acylated ghrelin administration. Overall, our studies suggest that acylated ghrelin is the isoform responsible for in vivo neuroprotection and that pharmacological approaches preventing plasma conversion from acyl ghrelin to des-acyl ghrelin may have clinical efficacy to help slow or prevent the debilitating effects of PD. Ghrelin exists in the plasma as acyl and des-acyl ghrelin. We determined the form responsible for in vivo neuroprotection in a mouse model of Parkinson's disease. Although exogenous acyl ghrelin is deacylated in situ to des-acyl, only acyl ghrelin was neuroprotective by attenuating dopamine cell loss and glial activation. Acyl ghrelin is a therapeutic option to reduce Parkinson's Disease progression. Cover Image for this issue: doi: 10.1111/jnc.13316.
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bayliss
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia.
authors.forename: Moyra
authors.initials: M
authors.lastname: Lemus
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia.
authors.forename: Vanessa V
authors.initials: VV
authors.lastname: Santos
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia.
authors.forename: Minh
authors.initials: M
authors.lastname: Deo
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Elsworth
authors.affiliation: Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia.
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D054439:Ghrelin / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020267:MPTP Poisoning / Q000517:prevention & control*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000473:pathology; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010302:Parkinson Disease, Secondary / Q000517:prevention & control*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D054439:Ghrelin; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; C528900:glial fibrillary astrocytic protein, mouse; D014446:Tyrosine 3-Monooxygenase; D000217:Acyltransferases; C526983:Mboat4 protein, mouse
keywords: GOAT; Parkinson's disease; acylated ghrelin; corticosterone; des-acylated ghrelin; dopamine