Williamson L C, Neale E A
Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480, USA.
J Neurosci Res. 1998 Jun 1;52(5):569-83. doi: 10.1002/(SICI)1097-4547(19980601)52:5<569::AID-JNR9>3.0.CO;2-A.
The Clostridium botulinum neurotoxins (BoNTs) A and C1 cleave specific proteins required for neuroexocytosis. We demonstrated that, in intact 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, we compare the actions of BoNT A and BoNT C1 on mature and developing mouse 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, dendrites, and cell bodies degenerate. Electron microscopy confirms that early degenerative changes occur in synaptic terminals when the somatic cytoplasm appears normal. In newly plated cultures, few neurons survive exposure to BoNT C1. Whereas both BoNT A and BoNT C1 cleave SNAP-25, BoNT A has no adverse effect on neurite outgrowth, synaptogenesis, or neuron survival. This cytotoxicity is unique to BoNT C1, is specific to neurons, and is initiated at the synaptic terminal, suggesting either a novel role for syntaxin or additional actions of BoNT C1. The neurodegeneration induced by BoNT C1 may be significant in terms of its efficacy for the clinical treatment of dystonia and spasticity.
肉毒杆菌神经毒素A（BoNT A）和C1（BoNT C1）可切割神经递质释放所需的特定蛋白质。我们已证明，在完整的神经元中，BoNT A可切割25 kDa的突触体相关蛋白（SNAP - 25），而BoNT C1可切割 syntaxin和SNAP - 25（Williamson等人：《分子生物学细胞》6:61a，1995；《生物化学杂志》271:7694 - 7699，1996）。在此，我们比较了BoNT A和BoNT C1对细胞培养中成熟和发育中的小鼠脊髓神经元的作用，并证明BoNT C1具有严重的神经毒性。在成熟培养物中，BoNT C1作用后不久突触终末会增大，随后轴突、树突和细胞体会退化。电子显微镜证实，当体细胞胞质看起来正常时，突触终末会出现早期退化变化。在新接种的培养物中，很少有神经元能在暴露于BoNT C1后存活。虽然BoNT A和BoNT C1都能切割SNAP - 25，但BoNT A对神经突生长、突触形成或神经元存活没有不利影响。这种细胞毒性是BoNT C1特有的，对神经元具有特异性，且始于突触终末，这表明syntaxin可能具有新功能，或者BoNT C1还有其他作用。就其对肌张力障碍和痉挛的临床治疗效果而言，BoNT C1诱导的神经变性可能具有重要意义。
