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

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Fibroblast Growth Factor (FGF) signaling is implicated in neurological and psychiatric disorders, but its specific role in pathogenesis remains unclear.
• Increased FGF1, FGF2, and FGF9 expression is observed during multiple sclerosis (MS) lesion development.
• FGF9 is also selectively upregulated in major depressive disorder (MDD), suggesting a direct impact on neuronal function and survival.

Purpose of the Study:

• To investigate the specific effects of FGF9 on neuronal function, survival, and its role in neurodegenerative disease pathogenesis.
• To explore the potential of targeting FGF9-dependent pathways for therapeutic intervention in MS, MDD, and other neurodegenerative conditions.

Main Methods:

• Transcriptional profiling of myelinating cultures treated with FGF1, FGF2, or FGF9.
• Investigating FGF9 effects on cortical neurons using transcriptional, electrophysiological, and immunofluorescence techniques.
• In vivo studies involving stereotactic injection of adeno-associated viral (AAV) vectors encoding FGF9 or EGFP into the rat motor cortex.

Main Results:

• FGF9 treatment downregulated gene networks associated with axonal transport and synaptic function in myelinating cultures.
• In cortical neurons, FGF9 rapidly reduced synaptic function gene expression, blocked photo-inducible spiking activity, and induced cell death.
• In vivo overexpression of FGF9 led to rapid neuronal loss, chronic grey matter lesions, neuroaxonal reduction, and myelin loss.

Conclusions:

• Overexpression of FGF9 can drive neuroaxonal pathology independently of immune-mediated demyelination in MS.
• Targeting neuronal FGF9-dependent pathways presents a novel therapeutic strategy to mitigate neuroaxonal atrophy and loss in MS, MDD, and other neurodegenerative diseases.