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Title: Natural and synthetic GHSR1a agonists as neuroprotective agents in models of Parkinson's disease
Author: Rees, Daniel J.
ISNI:       0000 0004 7425 5153
Awarding Body: Swansea University
Current Institution: Swansea University
Date of Award: 2017
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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in humans. It is characterised by the progressive loss of the A9 (Girk2+) subpopulation of dopamine (DA) neurones in the Substantia Nigra Pars Compacta (SNpc) resulting in resting tremor, bradykinesia and rigidity. The majority of PD cases are idiopathic. However, environmental toxins that inhibit the mitochondrial electron transport chain cause PD-like symptoms and recent studies of rare familial PD implicate metabolic dysfunction as a possible cause of DA nerve cell loss. We propose that the homeostatic hormone, acyl-ghrelin, may prevent DA neurone loss by preserving nerve cell metabolism during bioenergetics stress. In the in-vivo MPTP-toxin model of PD acyl-ghrelin prevents SNpc DA neurone loss in an acyl-ghrelin receptor (GHSR)-dependent manner (Andrews et al.2009). Here, using the eGFP-GHSR reporter mouse we demonstrate co-localised expression of the GHSR with TH+ and Girk2+ SNpc neurones. This suggests that acyl-ghrelin may exert a direct protective effect on A9 DA neurones via GHSR+ signalling. We show that acyl-ghrelin attenuated the 6-OHDA-induced SN lesion in unilateral lesioned rats. Moreover, this neuroprotection is consistent with the preservation of motor function. Using a mouse-midbrain-derived neuronal cell line (SN4741), immune-positive for TH+/ Girk2+/GHSR+, we assess the neuroprotective potential of acyl-ghrelin and GHSR1a agonist, JMV2894, in an in-vitro rotenone-based PD model. Furthermore, we show acyl-ghrelin as a modulator of intra-cellular AMPK and ACC phosphorylation and investigate the protective effects on mitochondrial health and morphology using automated images analysis and TEM. Acyl-ghrelin activated cellular pathways associated with protecting against energetic stress and promoting healthy aging. These data suggest that Acyl-Ghrelin may be a potential new therapeutic target for PD.
Supervisor: Davies, Jeffrey S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral