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 is 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 (GFAP) and Ionized calcium binding adaptor molecule 1 (IBA1) 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, GFAP and IBA1 cell number. The lack of a protective effect was mirrored in Ghrelin-O-Acyltransferase (GOAT) 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 GOAT 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. This article is protected by copyright. All rights reserved.