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

Thümmler, K., Wrzos, C., Franz, J., McElroy, D., Cole, J. J., Hayden, L., 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.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-E5A5-6 Version Permalink: https://hdl.handle.net/21.11116/0000-000E-34F5-3
Genre: Journal Article

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Neuropathology Appl Neurobio - 2023 - Th mmler - Fibroblast growth factor 9 FGF9 ‐mediated neurodegeneration Implications.pdf (Publisher version), 5MB
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 Creators:
Thümmler, Katja, Author
Wrzos, Claudia, Author
Franz, Jonas1, Author
McElroy, Daniel, Author
Cole, John J., Author
Hayden, Lorna, Author
Arseni, Diana, Author
Schwarz, Friedrich, Author
Junker, Andreas, Author
Edgar, Julia M., Author
Kügler, Sebastian, Author
Neef, Andreas1, Author
Wolf, Fred1, Author
Stadelmann, Christine, Author
Linington, Christopher, Author
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1Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3349219              

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 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. Lesiondevelopment 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 orFGF9 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 FGF9in 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

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Language(s): eng - English
 Dates: 2023-09-132023-10
 Publication Status: Issued
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1111/nan.12935
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Title: Neuropathology and Applied Neurobiology
  Other : Neuropathol. Appl. Neurobiol.
Source Genre: Journal
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Publ. Info: Oxford : Blackwell Scientific Publications.
Pages: 17 Volume / Issue: 49 (5) Sequence Number: e12935 Start / End Page: - Identifier: ISSN: 0305-1846
CoNE: https://pure.mpg.de/cone/journals/resource/954925513475