Simulations of active zone structure and function at mammalian NMJs predict that loss of calcium channels alone is not sufficient to replicate LEMS effects
Simulations of active zone structure and function at mammalian NMJs predict that loss of calcium channels alone is not sufficient to replicate LEMS effects
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DOI：
10.1152/jn.00404.2022
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发表时间：
2023-05-01
影响因子：
2.5
通讯作者：
Meriney，Stephen D.
中科院分区：
文献类型：
--
作者：
Ginebaugh，Scott P.;Badawi，Yomna;Meriney，Stephen D.
Lambert-Eaton肌无力综合征（LEMS）是一种自身免疫介导的神经肌肉疾病，被认为是由针对P/Q型电压门控钙通道（VGCC）的自身抗体引起的，其攻击神经肌肉接头（NMJ）的递质释放部位（活动区; AZ）内的VGCC并减少其数量，导致神经肌肉无力。然而，LEMS患者也有其他神经元蛋白的抗体，约15%的LEMS患者对VGCC抗体呈血清阴性。我们假设，P/Q型VGCC数量的减少不足以解释LEMS对递质释放的影响。在这里，我们使用了一个计算模型来研究各种LEMS介导的影响AZ组织和递质释放的电子显微镜，药理学，免疫组织化学，电压成像和电生理观察的约束。我们表明，健康AZ的模型可以被修改，以预测LEMS的递质释放和短期易化特征，除了AZ VGCC数量的减少，AZ蛋白组织的破坏，AZ数量的减少，突触结合蛋白数量的减少，和L型通道的代偿性表达是LEMS介导的递质释放效应的重要贡献者。此外，我们的模型预测，抗体介导的突触结合蛋白的去除结合单独的AZ组织的破坏可以模拟LEMS效应而不去除VGCC（血清阴性模型）。总的来说，我们的研究结果表明，LEMS的病理生理可能是由一个收集的病理改变AZ在NMJ，而不是由一个简单的损失VGCCs.NEW &值得注意的是，我们使用了计算模型的活动区（AZ）在哺乳动物神经肌肉接头调查兰伯特-伊顿肌无力综合征（LEMS）的病理生理。该模型表明，突触前活动区组织和蛋白质含量（特别是synaptotagmin）的中断，超越简单的突触前钙通道的清除，在LEMS的病理生理学中发挥重要作用。
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disease thought to be caused by autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs), which attack and reduce the number of VGCCs within transmitter release sites (active zones; AZs) at the neuromuscular junction (NMJ), resulting in neuromuscular weakness. However, patients with LEMS also have antibodies to other neuronal proteins, and about 15% of patients with LEMS are seronegative for antibodies against VGCCs. We hypothesized that a reduction in the number of P/Q-type VGCCs alone is not sufficient to explain LEMS effects on transmitter release. Here, we used a computational model to study a variety of LEMS-mediated effects on AZ organization and transmitter release constrained by electron microscopic, pharmacological, immunohistochemical, voltage imaging, and electrophysiological observations. We show that models of healthy AZs can be modified to predict the transmitter release and short-term facilitation characteristics of LEMS and that in addition to a decrease in the number of AZ VGCCs, disruption in the organization of AZ proteins, a reduction in AZ number, a reduction in the amount of synaptotagmin, and the compensatory expression of L-type channels outside the remaining AZs are important contributors to LEMS-mediated effects on transmitter release. Furthermore, our models predict that antibody-mediated removal of synaptotagmin in combination with disruption in AZ organization alone could mimic LEMS effects without the removal of VGCCs (a seronegative model). Overall, our results suggest that LEMS pathophysiology may be caused by a collection of pathological alterations to AZs at the NMJ, rather than by a simple loss of VGCCs.NEW & NOTEWORTHYWe used a computational model of the active zone (AZ) in the mammalian neuromuscular junction to investigate Lambert-Eaton myasthenic syndrome (LEMS) pathophysiology. This model suggests that disruptions in presynaptic active zone organization and protein content (particularly synaptotagmin), beyond the simple removal of presynaptic calcium channels, play an important role in LEMS pathophysiology.