Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis?
fibroblast growth factor 9
major depressive disorder
multiple sclerosis
neurodegeneration
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
revised:
22
08
2023
received:
12
02
2023
accepted:
10
09
2023
medline:
30
10
2023
pubmed:
14
9
2023
entrez:
14
9
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Substances chimiques
Fibroblast Growth Factor 1
104781-85-3
Fibroblast Growth Factor 2
103107-01-3
Fibroblast Growth Factor 9
0
Fgf9 protein, rat
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12935Subventions
Organisme : Ministry for Science and Culture of Lower Saxony
Organisme : BCCN
ID : 01GQ1005A
Organisme : Gemeinnützige Hertie Stiftung
Organisme : Deutsche Forschungsgemeinschaft
ID : 408885537
Organisme : Deutsche Forschungsgemeinschaft
ID : CRC 1286, 889
Organisme : Deutsche Forschungsgemeinschaft
ID : SPP 2205
Organisme : Deutsche Forschungsgemeinschaft
ID : EXC 2067/1-390729940
Organisme : Deutsche Multiple Sklerose Gesellschaft
Organisme : Ministry for Science and Education of Lower Saxony
Organisme : Volkswagen Foundation
ID : ZN2632
Organisme : National Multiple Sclerosis Society
Organisme : Max-Planck-Gesellschaft
Organisme : Naomi Bramson Trust
Organisme : Alexander von Humboldt-Stiftung
Organisme : MS Society UK
Organisme : Medical Research Scotland
ID : PhD-1031-2016
Organisme : TENOVUS Scotland
Informations de copyright
© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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