Monash Arik, Tam Joseph, Rosen Osnat, Soreq Hermona
Department of Biotechnology, Israel Institute for Biological Research (IIBR), Ness Ziona, Israel.
Obesity and Metabolism Laboratory, Faculty of Medicine, Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
J Neurochem. 2025 Aug;169(8):e70187. doi: 10.1111/jnc.70187.
Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, exert their potent neuroparalytic effects by specifically targeting presynaptic cholinergic nerve terminals. BoNTs consist of a heavy chain that mediates high-affinity neuronal binding and endocytosis, and a light chain that, once translocated into the cytosol, acts as a zinc-dependent metalloprotease. The light chain cleaves SNARE proteins essential for synaptic vesicle fusion, thereby inhibiting acetylcholine release and leading to flaccid paralysis. This intoxication spans foodborne, wound, and infant botulism, all characterized by commonly observed heat-resistant endospores that enable bacterial survival under adverse conditions. BoNT intoxication induces flaccid paralysis, and both natural and synthetic neurotoxins disrupt neuronal communication by targeting synaptic components. However, BoNTs differ in their origin, mechanism of action, structure, and interactions. Clinical harnessing of non-poisoning low doses of BoNT/A and BoNT/B serotypes is used for alleviating symptoms of diverse diseases. Molecular engineering and clinical formulation enabled BoNTs optimization into pharmacologically safe and targeted therapeutic agents that replicate the selective neuronal silencing observed in their natural forms.
肉毒杆菌神经毒素（BoNTs）由肉毒梭菌产生，通过特异性作用于突触前胆碱能神经末梢发挥强大的神经麻痹作用。BoNTs由一条重链和一条轻链组成，重链介导高亲和力的神经元结合和内吞作用，轻链一旦转运到细胞质中，就作为一种锌依赖性金属蛋白酶发挥作用。轻链切割突触小泡融合所必需的SNARE蛋白，从而抑制乙酰胆碱释放并导致弛缓性麻痹。这种中毒包括食源性、创伤性和婴儿肉毒中毒，其共同特征是普遍存在耐热的内生孢子，使细菌能够在不利条件下存活。BoNT中毒会导致弛缓性麻痹，天然和合成神经毒素都通过作用于突触成分来破坏神经元通讯。然而，BoNTs在其来源、作用机制、结构和相互作用方面存在差异。临床上利用非中毒低剂量的BoNT/A和BoNT/B血清型来缓解各种疾病的症状。分子工程和临床配方使BoNTs优化为药理学上安全且有针对性的治疗药物，这些药物能够重现其天然形式中观察到的选择性神经元沉默。
