期刊
GENE THERAPY
卷 12, 期 2, 页码 108-119出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3302400
关键词
clostridial toxin; tetanus toxin; gene transfer; synaptic transmission; synaptobrevin; spinal cord
类别
资金
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [K08NS043305] Funding Source: NIH RePORTER
- NINDS NIH HHS [K08 NS43305] Funding Source: Medline
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 synaptobrevin 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.
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