Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies.
Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies.
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DOI：
10.1016/j.neuron.2020.10.012
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发表时间：
2021-01-06
期刊：
影响因子：
16.2
通讯作者：
Kavalali ET
中科院分区：
文献类型：
--
作者：
Alten B;Zhou Q;Shin OH;Esquivies L;Lin PY;White KI;Sun R;Chung WK;Monteggia LM;Brunger AT;Kavalali ET
SNARE（可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体）复合物由小突触蛋白、突触融合蛋白和SNAP 25组成，形成神经递质释放的必要融合机制。最近的研究报道了编码SNAP 25的基因中的几个突变作为具有不同临床表现的婴儿和儿童发育性和癫痫性脑病的致病因素。然而，目前尚不清楚SNAP 25突变如何引起这些疾病。在这里，我们表明，虽然SNAP 25的结构聚集突变引起相关的突触传递表型，自发神经递质释放的特定改变是一个关键因素，占疾病的异质性。重要的是，我们确定了一个单一的突变，增强自发释放，而不改变诱发释放，这表明异常的自发释放足以引起人类疾病。阿尔滕等人使用结构和电生理学方法显示SNAP 25变体如何引起临床异质性发育和癫痫性脑病。他们的研究确定异常的自发神经传递是罪魁祸首，并表明专门针对自发释放的疗法将有利于治疗这些难治性疾病。
SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex composed of synaptobrevin, syntaxin and SNAP25 forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that while structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans. Alten et al. show how SNAP25 variants give rise to clinically heterogeneous developmental and epileptic encephalopathies using structural and electrophysiological approaches. Their study identifies aberrant spontaneous neurotransmission as a culprit and suggests that therapies specifically targeting spontaneous release would be beneficial in treatment of these intractable disorders.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.7
作者：
Hoerder-Suabedissen, Anna;Korrell, Kim V.;Molnar, Zoltan
通讯作者：
Molnar, Zoltan
DOI：
10.1126/science.1224492
发表时间：
2012-09-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gao Y;Zorman S;Gundersen G;Xi Z;Ma L;Sirinakis G;Rothman JE;Zhang Y
通讯作者：
Zhang Y
影响因子：
64.5
作者：
GEPPERT, M;GODA, Y;SUDHOF, TC
通讯作者：
SUDHOF, TC
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L