Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome.
Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome.
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DOI：
10.1371/journal.pone.0184817
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Reist NE
中科院分区：
文献类型：
--
作者：
Shields MC;Bowers MR;Fulcer MM;Bollig MK;Rock PJ;Sutton BR;Vrailas-Mortimer AD;Lochmüller H;Whittaker RG;Horvath R;Reist NE
在化学物质传递过程中，突触蛋白的功能必须协调才能有效地释放神经递质。Synaptotagmin 2是人体神经肌肉接头处快速、同步释放神经递质的Ca2+传感器，最近被认为与一种与非进行性运动神经病相关的显性遗传性先天性肌无力综合征有关。在一个家族中，突触结合蛋白的C2B Ca 2+结合口袋内的脯氨酸残基被亮氨酸取代。该残基的功能意义以前没有研究过。在这里，我们表明，在计算机模拟预测破坏的C2B钙结合口袋，我们研究在果蝇中的同源突变的体内效应。当表达的天然synaptotagmin的情况下，这种突变是致命的，第一次证明，这个残基在synaptotagmin功能中起着至关重要的作用。为了实现与人类患者相似的表达，突变在携带野生型突触结合蛋白基因的一个拷贝的果蝇中表达。我们现在表明，携带这种突变的果蝇产生了与人类患者相似的神经和行为表现，并提供了对这些缺陷背后机制的深入了解。我们的果蝇研究支持这种突触结合蛋白点突变在疾病病因中的作用。
During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket of synaptotagmin is replaced by a leucine. The functional significance of this residue has not been investigated previously. Here we show that in silico modeling predicts disruption of the C2B Ca2+-binding pocket, and we examine the in vivo effects of the homologous mutation in Drosophila. When expressed in the absence of native synaptotagmin, this mutation is lethal, demonstrating for the first time that this residue plays a critical role in synaptotagmin function. To achieve expression similar to human patients, the mutation is expressed in flies carrying one copy of the wild type synaptotagmin gene. We now show that Drosophila carrying this mutation developed neurological and behavioral manifestations similar to those of human patients and provide insight into the mechanisms underlying these deficits. Our Drosophila studies support a role for this synaptotagmin point mutation in disease etiology.
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