Investigating the protective roles and regulatory mechanisms of Fibroblast Growth Factor 9 in Huntington’s disease

Abstract

Huntington’s disease (HD) is a heritable neurodegenerative disorder characterized by selective and progressive damage of medium spiny neurons in the striatum; and there is no cure for HD to date A type of fibroblast growth factor (FGF) FGF9 has been reported to play prosurvival roles in other neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) With many similarities in the cellular and pathological mechanisms that eventually cause cell death in neurodegenerative diseases we hypothesize that FGF9 might provide neuroprotective functions in HD In this study STHdhQ7/Q7 (WT) and STHdhQ111/Q111 (HD) striatal knock-in cell lines and R6/2 primary cortical neurons were used to examine the neuroprotective effects and mechanisms of action of FGF9 on cell death oxidative stress neuronal morphology and synaptic integrity in HD Results show that FGF9 not only enhances cell proliferation but also suppresses cell death alleviates oxidative stress enhances neuronal morphology and increases synaptic protein expressions FGF9 significantly upregulates glial cell line-derived neurotrophic factor (GDNF) upregulates an anti-apoptotic protein Bcl-xL decreases the expression of an apoptotic protein Bax and suppresses apoptotic marker cleaved caspase 3; mostly through activating NF-kB pathway in HD cells In addition FGF9 upregulates Nrf2 expression and activation increases Nrf2-ARE activity and subsequently upregulating downstream targets of Nrf2 including SOD2 GCLc and GR Furthermore FGF9 increases neurite outgrowth and neuron morphology proteins including βIII-tubulin MAP2A/B and GAP-43 protein expressions; and upregulates the expression of synaptic proteins including Synaptophysin and PSD-95 mostly through activating NF-kB pathway in HD cells FGF9 may function through ERK AKT and JNK pathways Especially ERK pathway plays a critical role to influence the effects of FGF9 on cell death oxidative stress neuronal morphology and synaptic integrity The results obtained in this study not only show the neuroprotective effects of FGF9 but more importantly clarify some critical mechanisms in HD cells further providing an insight for the therapeutic potential of FGF9 in HD

Date of Award	2019
Original language	English
Supervisor	Shang-Hsun Yang (Supervisor)