Motor neuron activity enhances the proteomic stress caused by autophagy defects in the target muscle.
Motor neuron activity enhances the proteomic stress caused by autophagy defects in the target muscle.
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DOI：
10.1371/journal.pone.0291477
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发表时间：
2024
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
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一些证据表明，神经元兴奋性的增加可以增强蛋白质组应激。例如，癫痫可增强由某些与神经变性有关的易聚集蛋白的表达引起的蛋白质组学应激。然而，关于神经元兴奋性增强的机制仍然存在未解之谜。在这里，我们测试了在特定的谷氨酸能突触（果蝇幼虫的神经肌肉连接处）增加神经元的兴奋性是否可以增强由内质网融合/GTPase基因atlastin （atl）突变引起的蛋白质组学应激。先前的研究表明，来自atl2零突变体的幼虫肌肉在自噬方面存在缺陷，并积累含有泛素的蛋白质聚集体（多ub聚集体）。为了确定神经元兴奋性的增加是否会增强由atl2引起的蛋白质组学应激，我们激活了神经元内trpa1编码的兴奋性通道。我们发现TrpA1激活对野生型肌肉中聚ub聚集体的积累没有影响，但显著增加了atl2肌肉中聚ub聚集体的数量。先前的研究表明，无论是神经元还是肌肉的atl损失都会增加肌肉的poly-UB聚集数量。我们发现，当atl从肌肉中移除时，神经元TrpA1激活增加了poly-UB聚集数量，而不是从神经元中移除。神经元TrpA1的激活增强了肌肉肌肉丧失所带来的其他表型，如蛹大小减小和活力降低。综上所述，这些结果表明，肌肉损失引起的蛋白质组应激通过增加神经元兴奋性而增强。
Several lines of evidence demonstrate that increased neuronal excitability can enhance proteomic stress. For example, epilepsy can enhance the proteomic stress caused by the expression of certain aggregation-prone proteins implicated in neurodegeneration. However, unanswered questions remain concerning the mechanisms by which increased neuronal excitability accomplishes this enhancement. Here we test whether increasing neuronal excitability at a particular identified glutamatergic synapse, the Drosophila larval neuromuscular junction, can enhance the proteomic stress caused by mutations in the ER fusion/GTPase gene atlastin (atl). It was previously shown that larval muscle from the atl2 null mutant is defective in autophagy and accumulates protein aggregates containing ubiquitin (poly-UB aggregates). To determine if increased neuronal excitability might enhance the increased proteomic stress caused by atl2, we activated the TrpA1-encoded excitability channel within neurons. We found that TrpA1 activation had no effect on poly-UB aggregate accumulation in wildtype muscle, but significantly increased poly-UB aggregate number in atl2 muscle. Previous work has shown that atl loss from either neuron or muscle increases muscle poly-UB aggregate number. We found that neuronal TrpA1 activation enhanced poly-UB aggregate number when atl was removed from muscle, but not from neuron. Neuronal TrpA1 activation enhanced other phenotypes conferred by muscle atl loss, such as decreased pupal size and decreased viability. Taken together, these results indicate that the proteomic stress caused by muscle atl loss is enhanced by increasing neuronal excitability.
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