Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination

Q. Teng, D. K. Tanase, J. K. Liu, M. E. Garrity-Moses, K. B. Baker, N. M. Boulis

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Clostridial neurotoxins have assumed increasing importance in clinical application. The toxin's light chain component (LC) inhibits synaptic transmission by digesting vesicle-docking proteins without directly altering neuronal health. To study the properties of LC gene expression in the nervous system, an adenoviral vector containing the LC of tetanus toxin (AdLC) was constructed. LC expressed in differentiated neuronal PC12 cells was shown to induce time- and concentration-dependent digestion of mouse brain synapto-brevin in vitro as compared to control transgene products. LC gene expression in the rat lumbar spinal cord disrupted hindlimb sensorimotor function in comparison to control vectors as measured by the Basso-Beattie-Bresnahan (BBB) scale (P<0.001) and rotarod assay (P<0.003). Evoked electromyography (EMG) showed increased stimulus threshold and decreased response current amplitude in LC gene-transferred rats. At the peak of functional impairment, neither neuronal TUNEL staining nor reduced motor neuron density could be detected. Spontaneous functional recovery was observed to parallel the cessation of LC gene expression. These results suggest that light chain gene delivery within the nervous system may provide a nondestructive means for focused neural inhibition to treat a variety of disorders related to excessive synaptic activity, and prove useful for the study of neural circuitry.

Original languageEnglish (US)
Pages (from-to)108-119
Number of pages12
JournalGene therapy
Volume12
Issue number2
DOIs
StatePublished - Jan 2005
Externally publishedYes

Bibliographical note

Funding Information:
We thank Thomas Binz, PhD of the Medizinische Hochschule, Hannover, Germany for providing anti-LC antibodies and Sean Sweeney, PhD of the University of California, San Francisco for providing plasmid DNA. We also thank Dr Michael Imperiale of the University of Michigan for providing the adenovirus vector. This work was supported by the National Institutes of Health KO8 Grant NS43305, the Amyotrophic Lateral Sclerosis Association, and the Christopher Reeves Paralysis Foundation.

Keywords

  • Clostridial toxin
  • Gene transfer
  • Spinal cord
  • Synaptic transmission
  • Synaptobrevin
  • Tetanus toxin

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