SV2 mediates entry of tetanus neurotoxin into central neurons.
SV2 mediates entry of tetanus neurotoxin into central neurons.
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DOI：
10.1371/journal.ppat.1001207
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发表时间：
2010-11-24
期刊：
影响因子：
6.7
通讯作者：
Chapman ER
中科院分区：
文献类型：
--
作者：
Yeh FL;Dong M;Yao J;Tepp WH;Lin G;Johnson EA;Chapman ER
Tetanus neurotoxin causes the disease tetanus, which is characterized by rigid paralysis. The toxin acts by inhibiting the release of neurotransmitters from inhibitory neurons in the spinal cord that innervate motor neurons and is unique among the clostridial neurotoxins due to its ability to shuttle from the periphery to the central nervous system. Tetanus neurotoxin is thought to interact with a high affinity receptor complex that is composed of lipid and protein components; however, the identity of the protein receptor remains elusive. In the current study, we demonstrate that toxin binding, to dissociated hippocampal and spinal cord neurons, is greatly enhanced by driving synaptic vesicle exocytosis. Moreover, tetanus neurotoxin entry and subsequent cleavage of synaptobrevin II, the substrate for this toxin, was also dependent on synaptic vesicle recycling. Next, we identified the potential synaptic vesicle binding protein for the toxin and found that it corresponded to SV2; tetanus neurotoxin was unable to cleave synaptobrevin II in SV2 knockout neurons. Toxin entry into knockout neurons was rescued by infecting with viruses that express SV2A or SV2B. Tetanus toxin elicited the hyper excitability in dissociated spinal cord neurons - due to preferential loss of inhibitory transmission - that is characteristic of the disease. Surprisingly, in dissociated cortical cultures, low concentrations of the toxin preferentially acted on excitatory neurons. Further examination of the distribution of SV2A and SV2B in both spinal cord and cortical neurons revealed that SV2B is to a large extent localized to excitatory terminals, while SV2A is localized to inhibitory terminals. Therefore, the distinct effects of tetanus toxin on cortical and spinal cord neurons are not due to differential expression of SV2 isoforms. In summary, the findings reported here indicate that SV2A and SV2B mediate binding and entry of tetanus neurotoxin into central neurons. Tetanus neurotoxin is one of the most deadly bacterial toxins known and is the causative agent for the disease tetanus, also known as lockjaw. Tetanus neurotoxin utilizes motor neurons as a means of transport in order to enter the spinal cord. Once in the spinal cord, the toxin leaves motor neurons and enters inhibitory neurons through a “Trojan-horse” strategy, thereby preventing the release of inhibitory neurotransmitters onto motor neurons. This causes hyper-excitability of the motor neuron and excessive release of acetylcholine at the neuromuscular junction, resulting in rigid paralysis. There is a major gap in our understanding of the mechanism by which tetanus neurotoxin enters neurons. In the current study we discovered that the “Trojan-horse”, utilized by tetanus neurotoxin to enter central neurons, corresponds to recycling synaptic vesicles. Furthermore, we discovered that SV2 is critical for the binding and entry of tetanus neurotoxin into these neurons. These findings will enable further development of drugs that antagonize the action of the toxin and will also aid in the development of drug delivery systems that target spinal cord neurons.
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影响因子：
56.9
作者：
Dong, M;Yeh, F;Chapman, ER
通讯作者：
Chapman, ER
影响因子：
2.9
作者：
Fu, Zhuji;Chen, Chen;Barbieri, Joseph T.;Kim, Jung-Ja P.;Baldwin, Michael R.
通讯作者：
Baldwin, Michael R.
影响因子：
2.9
作者：
Baldwin, Michael R.;Barbieri, Joseph T.
通讯作者：
Barbieri, Joseph T.
影响因子：
56.9
作者：
BAJJALIEH, SM;PETERSON, K;SCHELLER, RH
通讯作者：
SCHELLER, RH
影响因子：
4.8
作者：
Bohnert, S;Schiavo, G
通讯作者：
Schiavo, G