Fibroblast Growth Factor 9 Stimulates Neuronal Length Through NF-kB Signaling in Striatal Cell Huntington’s Disease Models

Abstract

Proper development of neuronal cells is important for brain functions, and impairment of neuronal development may lead to neuronal disorders, implying that improvement in neuronal development may be a therapeutic direction for these diseases. Huntington's disease (HD) is a neurodegenerative disease characterized by impairment of neuronal structures, ultimately leading to neuronal death and dysfunctions of the central nervous system. Based on previous studies, fibroblast growth factor 9 (FGF9) may provide neuroprotective functions in HD, and FGFs may enhance neuronal development and neurite outgrowth. However, whether FGF9 can provide neuronal protective functions through improvement of neuronal morphology in HD is still unclear. Here, we study the effects of FGF9 on neuronal morphology in HD and attempt to understand the related working mechanisms. Taking advantage of striatal cell lines from HD knock-in mice, we found that FGF9 increases neurite outgrowth and upregulates several structural and synaptic proteins under HD conditions. In addition, activation of nuclear factor kappa B (NF-kB) signaling by FGF9 was observed to be significant in HD cells, and blockage of NF-kB leads to suppression of these structural and synaptic proteins induced by FGF9, suggesting the involvement of NF-kB signaling in these effects of FGF9. Taken these results together, FGF9 may enhance neurite outgrowth through upregulation of NF-kB signaling, and this mechanism could serve as an important mechanism for neuroprotective functions of FGF9 in HD.

New developments in the biology of fibroblast growth factors

“…In Huntington's disease, FGF9 was shown to protect striatal cells in vitro by increasing proliferation and reducing cell death in response to starvation stress. FGF9 strongly induced expression of glial cell line-derived neurotrophic factor (GDNF), the anti-apoptotic marker, Bcl-xL, the anti-oxidative stress gene, nuclear factor erythroid 2-like 2 (Nrf2), and nuclear factor kappa B (NF-kB) signaling, through ERK signaling pathways (Yusuf et al, 2018(Yusuf et al, , 2019(Yusuf et al, , 2021.…”

The Role of Autophagy in Anti-Cancer and Health Promoting Effects of Cordycepin

“…HD is a polyglutamine disease caused by the translation of abnormally expanded cytosine-adenine-guanine (CAG) trinucleotides in the disease-causing gene Huntingtin . The abnormally expanded polyglutamines are misfolded and then form nuclear, intranuclear, and neuropil aggregates to disrupt cellular functions [ 108 , 109 , 110 ]. These polyglutamine expansions have been shown to regulate Beclin-1 to influence autophagy in different polyglutamine diseases [ 111 ], and the abnormal expansion of polyglutamines has been reported to disrupt Beclin-1 and autophagy to cause aggregates in HD [ 112 , 113 ].…”

Fibroblast growth factor 9 (FGF9)‐mediated neurodegeneration: Implications for progressive multiple sclerosis?

“…FGF9 is up regulated by oligodendrocytes and astrocytes at sites of ongoing tissue damage in MS [20, 21], where it was initially posited to exacerbate disease activity by inhibiting remyelination and/or up regulating expression of pro‐inflammatory chemokines or alternatively suppress disease progression by providing some degree of neuroprotection [20]. The latter outcome was suggested by reports FGF9 mediates neuroprotection in cellular models of Parkinson's and Huntington's disease [58–60]. However, this scenario is now considered unlikely, as our new data demonstrate increased availability of FGF9 compromises neuronal survival in vivo.…”