N4-acetylcytidine acetylation of neurexin 2 in the spinal dorsal horn regulates hypersensitivity in a rat model of cancer-induced bone pain

Molecular Therapy: Nucleic Acids, 2024 · DOI: https://doi.org/10.1016/j.omtn.2024.102200 · Published: June 1, 2024

Simple Explanation

Cancer-induced bone pain (CIBP) is a common and debilitating symptom for patients with advanced cancer. This study investigates the role of neurexin 2, a protein involved in nerve cell communication, in the development of CIBP. The research found that in a rat model of CIBP, neurexin 2 expression increased in spinal cord neurons. Reducing neurexin 2 levels reversed pain-related behaviors, decreased sensitization of spinal neurons, and improved negative emotional behaviors associated with pain. The study also identified increased acetylation of neurexin 2 mRNA in the spinal cord of CIBP rats. This acetylation, regulated by an enzyme called NAT10, enhances the stability of neurexin 2 mRNA, leading to increased neurexin 2 expression and ultimately, the remodeling of spinal synapses and the development of pain hypersensitivity.

Study Duration

Not specified

Participants

Female Sprague-Dawley rats

Evidence Level

Not specified

Key Findings

1
Neurexin 2 expression is significantly increased in the spinal dorsal horn (SDH) of rats with cancer-induced bone pain (CIBP), and this increase is correlated with lower pain thresholds.
2
Knockdown of neurexin 2 in the spinal cord reverses pain behavior, reduces spinal neuron sensitization, and improves pain-related negative emotional behaviors in CIBP rats.
3
NAT10-mediated acetylation of neurexin 2 mRNA enhances its stability and upregulates neurexin 2 expression, leading to increased neuronal synaptogenesis in the spinal cord of CIBP rats.

Research Summary

This study investigates the role of neurexin 2 in cancer-induced bone pain (CIBP), finding that its expression is increased in the spinal dorsal horn (SDH) of CIBP rats and correlates with pain hypersensitivity. The researchers demonstrated that N-acetyltransferase 10 (NAT10) regulates neurexin 2 mRNA acetylation and expression. Reducing NAT10 levels decreased neurexin 2 mRNA acetylation, thereby reducing neurexin 2 expression and alleviating pain-related behaviors. The study concludes that targeting the epigenetic modification of neurexin 2 mRNA ac4C may offer a new therapeutic approach for treating nociceptive hypersensitivity in CIBP.

Practical Implications

Therapeutic Target Identification

Neurexin 2 and NAT10 have been identified as potential therapeutic targets for managing cancer-induced bone pain.

Epigenetic Intervention

Targeting the epigenetic modification of neurexin 2 mRNA ac4C presents a novel approach for treating nociceptive hypersensitivity in CIBP.

Synaptic Plasticity Modulation

Modulating the NAT10/ac4C-neurexin 2 axis can help regulate synaptic morphology and the expression of synapse-associated proteins, providing a means to control pain sensitization.

Study Limitations

1
The study is based on a rat model, and findings may not directly translate to humans.
2
The precise mechanisms by which neurexin 2 contributes to synaptic plasticity require further investigation.
3
The study primarily focuses on female rats, and the potential differences in CIBP mechanisms between sexes are not fully explored.

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