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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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Datensatz-Permalink: https://hdl.handle.net/21.11116/0000-000D-E5A5-6 Versions-Permalink: https://hdl.handle.net/21.11116/0000-000E-34F5-3

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Neuropathology Appl Neurobio - 2023 - Th mmler - Fibroblast growth factor 9 FGF9 ‐mediated neurodegeneration Implications.pdf (Verlagsversion), 5MB

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Urheber:
Thümmler, Katja, Autor
Wrzos, Claudia, Autor
Franz, Jonas¹, Autor
McElroy, Daniel, Autor
Cole, John J., Autor
Hayden, Lorna, Autor
Arseni, Diana, Autor
Schwarz, Friedrich, Autor
Junker, Andreas, Autor
Edgar, Julia M., Autor
Kügler, Sebastian, Autor
Neef, Andreas¹, Autor
Wolf, Fred¹, Autor
Stadelmann, Christine, Autor
Linington, Christopher, Autor

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1Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3349219

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Zusammenfassung: 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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Sprache(n): eng - English

Datum: Online veröffentlicht: 2023-09-13Erschienen: 2023-10

Publikationsstatus: Erschienen

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Art der Begutachtung: Expertenbegutachtung

Identifikatoren: DOI: 10.1111/nan.12935

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Titel: Neuropathology and Applied Neurobiology

Andere : Neuropathol. Appl. Neurobiol.

Genre der Quelle: Zeitschrift

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Ort, Verlag, Ausgabe: Oxford : Blackwell Scientific Publications.

Seiten: 17 Band / Heft: 49 (5) Artikelnummer: e12935 Start- / Endseite: - Identifikator: ISSN: 0305-1846
CoNE: https://pure.mpg.de/cone/journals/resource/954925513475