Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats - Archive ouverte HAL Access content directly
Journal Articles Molecular Therapy Year : 2024

Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats

Marjorie Kerzonkuf
  • Function : Author
Jérémy Verneuil
  • Function : Author
Cécile Brocard
  • Function : Author
Nejada Dingu
  • Function : Author
Virginie Trouplin
  • Function : Author
Jose Jorge Ramirez Franco
  • Function : Author
Marc Bartoli
  • Function : Author
Frédéric Brocard
  • Function : Author
Hélène Bras

Abstract

Spasticity, affecting ∼75% of patients with spinal cord injury (SCI), leads to hyperreflexia, muscle spasms, and cocontractions of antagonist muscles, greatly affecting their quality of life. Spasticity primarily stems from the hyperexcitability of motoneurons below the lesion, driven by an upregulation of the persistent sodium current and a downregulation of chloride extrusion. This imbalance results from the post-SCI activation of calpain1, which cleaves Nav1.6 channels and KCC2 cotransporters. Our study was focused on mitigating spasticity by specifically targeting calpain1 in spinal motoneurons. We successfully transduced lumbar motoneurons in adult rats with SCI using intrathecal administration of adeno-associated virus vector serotype 6, carrying a shRNA sequence against calpain1. This approach significantly reduced calpain1 expression in transduced motoneurons, leading to a noticeable decrease in spasticity symptoms, including hyperreflexia, muscle spasms, and cocontractions in hindlimb muscles, which are particularly evident in the second month post-SCI. In addition, this decrease, which prevented the escalation of spasticity to a severe grade, paralleled the restoration of KCC2 levels in transduced motoneurons, suggesting a reduced proteolytic activity of calpain1. These findings demonstrate that inhibiting calpain1 in motoneurons is a promising strategy for alleviating spasticity in SCI patients.

Dates and versions

hal-04538561 , version 1 (09-04-2024)

Identifiers

Cite

Marjorie Kerzonkuf, Jérémy Verneuil, Cécile Brocard, Nejada Dingu, Virginie Trouplin, et al.. Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats. Molecular Therapy, 2024, 32 (4), pp.1096-1109. ⟨10.1016/j.ymthe.2024.01.029⟩. ⟨hal-04538561⟩
8 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More