Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240-7933, USA.
Neuron. 2021 Jan 6;109(1):59-72.e5. doi: 10.1016/j.neuron.2020.10.012. Epub 2020 Nov 3.
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 although 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.
突触融合蛋白（SNAP）受体复合物由突触融合蛋白、突触融合相关蛋白和 SNAP25 组成，是神经递质释放的必需融合机制。最近的研究报道了编码 SNAP25 的基因突变是婴儿和儿童发育性和癫痫性脑病的致病因素，具有不同的临床表现。然而，尚不清楚 SNAP25 突变如何导致这些疾病。在这里，我们表明，尽管 SNAP25 的结构聚集性突变导致相关的突触传递表型，但自发性神经递质释放的特定改变是解释疾病异质性的关键因素。重要的是，我们鉴定出一个单一的突变可以增强自发性释放而不改变诱发释放，表明异常的自发性释放足以导致人类疾病。
