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Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
FGF13 Deficiency Ameliorates Paclitaxel-Induced Neuropathic Pain by Inhibiting VASH1-Mediated Microtubule
Yiming Dong1, Yidan Wang1, Simeng Lv1
1Key Laboratory of New Drug Pharmacology and Toxicology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China.
Abstract:
Mitochondrial damage in dorsal root ganglion (DRG) neurons contributes to the pathogenesis of paclitaxel (PTX)-induced peripheral neuropathic pain (PIPNP). Fibroblast growth factor 13 (FGF13), abundantly expressed in DRG neurons, is crucial for the regulation of somatosensation; however, its role in PIPNP remains unclear. Here, we demonstrated that FGF13 expression is upregulated in DRG neurons of PIPNP model mice. Conditional knockout of Fgf13 in DRG neurons effectively alleviates PTX-induced mitochondrial damage and neuropathic pain. RNA sequencing analysis revealed that mitophagy mediates the regulatory effects of FGF13 in PIPNP. Mechanistically, FGF13 physically interacts with vasohibin 1 (VASH1), regulating the binding of VASH1 to microtubules and promoting microtubule detyrosination. FGF13 ablation disrupts assembly of the FGF13-VASH1-α-tubulin ternary complex, impairing VASH1-mediated microtubule detyrosination and increasing microtubule tyrosination. The resulting accumulation of tyrosinated microtubules facilitates kinesin-3 (KIF1A)-driven lysosomal trafficking, which in turn promotes mitophagy activation and ultimately ameliorates PTX-induced mitochondrial damage and PIPNP. Furthermore, VASH1 overexpression in DRG neurons reversed the alleviating effects of FGF13 deficiency on PTX-induced mitochondrial damage and PIPNP. In summary, our findings demonstrate that FGF13 deficiency alleviates mitochondrial dysfunction and PIPNP by suppressing VASH1-dependent microtubule detyrosination and subsequently activating mitophagy. Targeting FGF13 may be a promising therapeutic strategy for PIPNP.
Insights
Fibroblast growth factor 13 (FGF13) deficiency alleviates paclitaxel-induced neuropathic pain by reducing mitochondrial damage. This occurs through regulating microtubule detyrosination and activating mitophagy in dorsal root ganglion neurons.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Mitochondrial damage in dorsal root ganglion (DRG) neurons is a key factor in paclitaxel (PTX)-induced peripheral neuropathic pain (PIPNP).
- Fibroblast growth factor 13 (FGF13), vital for somatosensation, has an unclear role in PIPNP.
Purpose of the Study:
- To investigate the role of FGF13 in PIPNP pathogenesis.
- To elucidate the molecular mechanisms by which FGF13 influences neuropathic pain and mitochondrial function.
Main Methods:
- Utilized a mouse model of PTX-induced neuropathic pain.
- Performed conditional knockout of Fgf13 in DRG neurons.
- Conducted RNA sequencing analysis to identify molecular pathways.
- Investigated protein-protein interactions (FGF13, VASH1, α-tubulin) and microtubule detyrosination.
- Assessed mitophagy activation and lysosomal trafficking.
Main Results:
- FGF13 expression was upregulated in DRG neurons of PIPNP mice.
- Conditional knockout of Fgf13 alleviated PTX-induced mitochondrial damage and neuropathic pain.
- FGF13 interacts with VASH1, regulating microtubule detyrosination; FGF13 deficiency impairs this process.
- FGF13 deficiency promotes mitophagy activation via altered microtubule tyrosination and KIF1A-driven trafficking.
- VASH1 overexpression reversed the protective effects of FGF13 deficiency.
Conclusions:
- FGF13 deficiency ameliorates PIPNP and mitochondrial dysfunction by suppressing VASH1-dependent microtubule detyrosination and activating mitophagy.
- Targeting FGF13 presents a potential therapeutic strategy for managing PIPNP.
