SYNTAXIN AND 25-KDA SYNAPTOSOMAL-ASSOCIATED PROTEIN - DIFFERENTIAL-EFFECTS OF BOTULINUM NEUROTOXINS C1 AND NEUROTOXIN-A ON NEURONAL SURVIVAL

The Clostridium botulinum neurotoxins (BoNTs) A and C1 cleave specific proteins required for neuroexocytosis. We demonstrated that, in intac t neurons, BoNT A cleaves 25-kDa synaptosomal-associated protein (SNAP -25), and BoNT C1 cleaves both syntaxin and SNAP-25 (Williamson et al, : Mol Biol Cell 6:61a, 1995; J Biol Chem 271:7694-7699, 1996), Here, w e compare the actions of BoNT A and BoNT C1 on mature and developing m ouse spinal cord neurons in cell culture and demonstrate that BoNT C1 is severely neurotoxic. In mature cultures, synaptic terminals become enlarged shortly after BoNT C1 exposure, and, subsequently, axons, den drites, and cell bodies degenerate, Electron microscopy confirms that early degenerative changes occur in synaptic terminals when the somati c cytoplasm appears normal. In newly plated cultures, few neurons surv ive exposure to BoNT C1, Whereas both BoNT A and BoNT C1 cleave SNAP-2 5, BoNT A has no adverse effect on neurite outgrowth, synaptogenesis, or neuron survival, This cytotoxicity is unique to BoNT C1, is specifi c to neurons, and is initiated at the synaptic terminal, suggesting ei ther a novel role for syntaxin or additional actions of BoNT C1, The n eurodegeneration induced by BoNT C1 may be significant in terms of its efficacy for the clinical treatment of dystonia and spasticity. (C) 1 998 Wiley-Liss, Inc. dagger.