Abstract
Adult hippocampal neurogenesis—the generation of new functional neurones in the adult brain—is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits it, thus demonstrating a previously unknown function of unacyl-ghrelin in modulating hippocampal plasticity. Analysis of plasma samples from Parkinson’s disease patients with dementia demonstrated a reduced acyl-ghrelin:unacyl-ghrelin ratio compared to both healthy controls and cognitively intact Parkinson’s disease patients. These data, from mouse and human studies, suggest that restoring acyl-ghrelin signalling may promote the activation of pathways to support memory function. In this short review, we discuss the evidence for ghrelin’s role in regulating adult hippocampal neurogenesis and the enzymes involved in ghrelin acylation and de-acylation as targets to treat mood-related disorders and dementia.
Highlights
The gut hormone ghrelin was identified as the natural ligand of the growth hormone secretagogue receptor 1a (GHS-R1a) in 1999 [1]
Treatment of ghrelinO-acyl transferase (GOAT)−/− mice with acyl-ghrelin once daily for 7 days restored performance to WT levels [47]. These data suggest that acyl-ghrelin signalling is activating both neurogenic and other hippocampal pathways to support memory function and is consistent with previous studies identifying enhanced hippocampal long-term potentiation (LTP) [7,53,54], increased expression of GluA1-containing amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [55], as well as the phosphoGluN2B [56] and the NR2B subunit of the N-methyl-D-aspartate receptor (NMDA) receptor [57], in response to acyl-ghrelin
We reported that the expression of GHSR-1a mRNA in the adult human hippocampal granule cell layer (GCL) remained unaltered across the three experimental groups tested [47]
Summary
The gut hormone ghrelin was identified as the natural ligand of the growth hormone secretagogue receptor 1a (GHS-R1a) in 1999 [1]. Human ghrelin, encoded by the GHRL gene, generates the 117-amino-acid preproghrelin peptide that is enzymatically processed to the native 28-amino-acid peptide, unacyl-ghrelin (UAG). UAG undergoes enzymatic modification in the endoplasmic reticulum by ghrelinO-acyl transferase (GOAT) to generate acyl-ghrelin, the so-called active form of the hormone [14,15]. This post-translational modification includes the addition of a medium-chain fatty acid (generally octanoic acid) at Serine residue 3 (Ser3), which is essential to bind and activate GHS-R1a signalling [16]. Ghrelin is the only known peptide that requires a fatty acid modification to regulate binding to its cognate receptor.
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