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

• Published in: Neuropathology and applied neurobiology 2023-10, Vol.49 (5), p.e12935-n/a
• Main Authors: Thümmler, Katja, Wrzos, Claudia, Franz, Jonas, McElroy, Daniel, Cole, John J., Hayden, Lorna, Arseni, Diana, Schwarz, Friedrich, Junker, Andreas, Edgar, Julia M., Kügler, Sebastian, Neef, Andreas, Wolf, Fred, Stadelmann, Christine, Linington, Christopher
• Format: Article
• Language: English
• Subjects: Atrophy; Axonal transport; Cell death; Cortex (motor); Demyelination; Down-regulation; Fibroblast growth factor 1; Fibroblast growth factor 2; Fibroblast growth factor 9; Fibroblast growth factor receptor 9; Fibroblast growth factors; Fibroblasts; Firing pattern; Growth factors; Immunofluorescence; major depressive disorder; Mental depression; Multiple sclerosis; Myelin; Myelination; neurodegeneration; Neurodegenerative diseases; Rhodopsin; Signal transduction; Substantia grisea; Transcription
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12935

Aims Fibroblast growth factor (FGF) signalling is dysregulated in multiple sclerosis (MS) and other neurological and psychiatric conditions, but there is little or no consensus as to how individual FGF family members contribute to disease pathogenesis. Lesion development in MS is associated with increased expression of FGF1, FGF2 and FGF9, all of which modulate remyelination in a variety of experimental settings. However, FGF9 is also selectively upregulated in major depressive disorder (MDD), prompting us to speculate it may also have a direct effect on neuronal function and survival. Methods Transcriptional profiling of myelinating cultures treated with FGF1, FGF2 or FGF9 was performed, and the effects of FGF9 on cortical neurons investigated using a combination of transcriptional, electrophysiological and immunofluorescence microscopic techniques. The in vivo effects of FGF9 were explored by stereotactic injection of adeno‐associated viral (AAV) vectors encoding either FGF9 or EGFP into the rat motor cortex. Results Transcriptional profiling of myelinating cultures after FGF9 treatment revealed a distinct neuronal response with a pronounced downregulation of gene networks associated with axonal transport and synaptic function. In cortical neuronal cultures, FGF9 also rapidly downregulated expression of genes associated with synaptic function. This was associated with a complete block in the development of photo‐inducible spiking activity, as demonstrated using multi‐electrode recordings of channel rhodopsin‐transfected rat cortical neurons in vitro and, ultimately, neuronal cell death. Overexpression of FGF9 in vivo resulted in rapid loss of neurons and subsequent development of chronic grey matter lesions with neuroaxonal reduction and ensuing myelin loss. Conclusions These observations identify overexpression of FGF9 as a mechanism by which neuroaxonal pathology could develop independently of immune‐mediated demyelination in MS. We suggest targeting neuronal FGF9‐dependent pathways may provide a novel strategy to slow if not halt neuroaxonal atrophy and loss in MS, MDD and potentially other neurodegenerative diseases. Multiple sclerosis and Major Depressive Disorder are associated with increased expression of FGF9 in affected brain regions. We now report that FGF9 is neurotoxic, as it rapidly down regulates neuronal gene networks required to maintain synaptic function and axonal transport and compromises survival of post‐mitotic neurons. FGF9 overexpr