Neuroprotective Effects of FGF20 on Dopamine Neurones

Abstract

Recent findings have demonstrated fibroblast growth factor-20 (FGF20) to have neuroprotective effects on dopamine neurones in vitro. In this thesis, FGF20’s neuroprotective effects on dopamine neurones were further investigated. A ventral mesencephalic (VM) embryonic dopamine neurone culture system and a partially lesioned 6-hydroxydopamine (6OHDA) rat model of Parkinson’s disease (PD) were established in which FGF20 was evaluated for its neuroprotective effects both in vitro and in vivo. Using immunohistochemistry, FGF20 and at least three of its receptors (fibroblast growth factor receptor (FGFR) 1,3, and 4) were demonstrated to be localised to dopamine neurones and glial cells in the rat nigrostriatal tract and in VM embryonic dopamine neurone cultures. In vitro, FGF20 protected VM embryonic dopamine neurones against 6OHDA toxicity, and, in vivo, chronic supra-nigral delivery of FGF20 protected nigrostriatal dopamine neurones against a partial 6OHDA lesion. Importantly, FGF20 also preserved motor function in the 6OHDA lesioned rats. In a separate in vivo study, experiments were carried out to investigate whether pharmacological inhibition of FGFR activation is able to potentiate 6OHDA-induced nigrostriatal degeneration in the rat, and results from this study suggest that the endogenous FGF system might play a protective role in the nigrostriatal tract. Additionally, in PC 12 cells, FGF20’s neuroprotective effects against 6OHDA toxicity were demonstrated to be mediated by the FGFRs at the receptor level, and by the ERK1/2 MAPK pathway at the intracellular level. Others have shown the heparin sulphate proteoglycan, agrin to potentiate FGF2 stimulated ERK1/2 activation and neurite outgrowth in PC12 cells. It was demonstrated here that agrin potentiates FGF20 stimulated ERK1/2 activation, but it fails to potentiate FGF20’s neuroprotective effects in PC12 cells.

Date of Award	1 May 2012
Original language	English
Awarding Institution	King's College London
Supervisor	Susan Duty (Supervisor) & Robert Williams (Supervisor)