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

Thümmler, K. et al. (2023) Fibroblast growth factor 9 (FGF9) mediated neurodegeneration: implications for progressive multiple sclerosis? Neuropathology and Applied Neurobiology, 49(5), e12935. (doi: 10.1111/nan.12935) (PMID:37705188)

Abstract

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.

• Item Type: Articles
• Additional Information: This study was supported by the Gemeinnützige Hertie Stiftung (C.L. and C.S.), the Deutsche Forschungsgemeinschaft (DFG) transregional collaborative research centers (CRCs) 43 “The brain as a target of inflammatory processes” and 274 “Checkpoints of CNS recovery” Project ID 408885537, the DFG under Germany’s Excellence Strategy (EXC 2067/1- 390729940), the Deutsche Multiple Sklerose Gesellschaft (DMSG), the Ministry for Science and Education of Lower Saxony and the Volkswagen Foundation (“Niedersächsisches Vorab”) and the National MS Society (USA), to C.S.. J.F. is supported by the clinician scientist program of the CRC274; F.W. by VW Foundation (ZN2632), BCCN (01GQ1005A and 01GQ1005B), DFG (CRC 1286, 889; SPP 2205), the Ministry for Science and Culture of Lower Saxony, and the Max Planck Society; C.L. by Naomi Bramson Trust and Alexander von Humboldt-Stiftung, K.T. and C.L. by MS Society UK; L.H. and D.A. by a PhD studentship from Medical Research Scotland (PhD -1031-2016); D.M. by a PhD studentship from MS Society UK, K.T. by TENOVUS Scotland.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Linington, Professor Chris and McElroy, Dr Daniel and Muecklisch, Dr Katja and Edgar, Professor Julia and Hayden, Lorna and Cole, Mr John
• Authors: Thümmler, K., Wrzos, C., Franz, J., McElroy, D., Cole, J. J., Hayden, L., Arseni, D., Schwarz, F., Junker, A., Edgar, J. M., Kügler, S., Neef, A., Wolf, F., Stadelmann, C., and Linington, C.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Neuropathology and Applied Neurobiology
• Publisher: Wiley
• ISSN: 0305-1846
• ISSN (Online): 1365-2990
• Published Online: 13 September 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Neuropathology and Applied Neurobiology 49(5):e12935
• Publisher Policy: Reproduced under a Creative Commons licence