Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A - Basis for distinct durations of inhibition of exocytosis in central neurons
Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A - Basis for distinct durations of inhibition of exocytosis in central neurons
复制标题
DOI：
10.1074/jbc.m209821200
复制
发表时间：
2003-01-10
影响因子：
4.8
通讯作者：
Dolly, JO
中科院分区：
文献类型：
--
作者：
Foran, PG;Mohammed, N;Dolly, JO
七种类型（A-G）的肉毒杆菌神经毒素（BoNT）靶向外周胆碱能神经元，其中它们选择性地蛋白水解SNAP-25（BoNT/A、BoNT/C1和BoNT/E）、突触融合蛋白1（BoNT/C1）和小突触蛋白（BoNT/B、BoNT/D、BoNT/F和BoNT/G），这些SNARE蛋白负责递质释放，以引起神经肌肉麻痹，但持续时间不同。BoNT/A麻痹在人类中持续时间最长（4-6个月），因此其广泛用于治疗肌张力障碍的临床用途。这些不同的抑制模式的分子机制在大鼠小脑神经元中被破译，通过定量的半衰期的影响，每种毒素的补充其底物的速度，和裂解产物的降解，实验不容易可行的运动神经末梢。靶切割与递质释放阻断的相关性产生了BoNT/A、BoNT/C1、BoNT/B、BoNT/F和BoNT/E的抑制半衰期（分别远大于31、远大于25、类似于10、类似于2和类似于0.8天），相当于小鼠中发现的神经肌肉麻痹时间，释放恢复与完整SNARE的再现一致。BoNT/F和BoNT/E的短神经麻痹持续时间的限制因素是小突触泡蛋白或SNAP-25的补充，而脉冲标记揭示了BoNT/A、BoNT/B或BoNT/C1的延长抑制是由每种蛋白酶的寿命引起的。这些新的发现可以帮助开发新的毒素疗法，用于对BoNT/A耐药的患者和对人类肉毒杆菌中毒的有效治疗。
Seven types (A-G) of botulinum neurotoxin (BoNT) target peripheral cholinergic neurons where they selectively proteolyze SNAP-25 (BoNT/A, BoNT/C1, and BoNT/E), syntaxin1 (BoNT/C1), and synaptobrevin (BoNT/B, BoNT/D, BoNT/F, and BoNT/G), SNARE proteins responsible for transmitter release, to cause neuromuscular paralysis but of different durations. BoNT/A paralysis lasts longest (4-6 months) in humans, hence its widespread clinical use for the treatment of dystonias. Molecular mechanisms underlying these distinct inhibitory patterns were deciphered in rat cerebellar neurons by quantifying the half-life of the effect of each toxin, the speed of replenishment of their substrates, and the degradation of the cleaved products, experiments not readily feasible at motor nerve endings. Correlation of target cleavage with blockade of transmitter release yielded half-lives of inhibition for BoNT/A, BoNT/C1, BoNT/B, BoNT/F, and BoNT/E (much greater than 31, much greater than 25, similar to10, similar to2, and similar to0.8 days, respectively), equivalent to the neuromuscular paralysis times found in mice, with recovery of release coinciding with reappearance of the intact SNAREs. A limiting factor for the short neuroparalytic durations of BoNT/F and BoNT/E is the replenishment of synaptobrevin or SNAP-25, whereas pulse labeling revealed that extended inhibition by BoNT/A, BoNT/B, or BoNT/C1 results from longevity of each protease. These novel findings could aid development of new toxin therapies for patients resistant to BoNT/A and effective treatments for human botulism.