Drosophila Atlastin regulates the stability of muscle microtubules and is required for synapse development
Drosophila Atlastin regulates the stability of muscle microtubules and is required for synapse development
复制标题
DOI：
10.1016/j.ydbio.2009.03.019
复制
发表时间：
2009-06-15
影响因子：
2.7
通讯作者：
Lee, Seungbok
中科院分区：
文献类型：
--
作者：
Lee, Mihye;Paik, Sang Kyoo;Lee, Seungbok
遗传性痉挛性截瘫（HSP）是一种以进行性痉挛和下肢无力为特征的遗传性神经系统疾病。最常见的早发型热休克是由编码动力蛋白家族GTPase Atlastin-1 （Atl-1）的人类基因突变引起的。最近，研究发现，果蝇中Atl-1 （Atl）同源基因的缺失会导致最早成年阶段的运动障碍，这表明atlastin亚家族GTPases在发育过程中起着重要作用。在这里，我们提供的证据表明，Ad是肌肉和神经肌肉连接处（NMJ）突触正常生长所必需的。Ad蛋白在幼虫体壁肌肉中高度表达。ad基因的功能缺失突变减少了肌肉的大小，增加了突触钮扣的数量。这些缺陷的修复是通过肌肉而不是神经元表达Ad来完成的。Ad的缺失也会破坏肌肉中的内质网和高尔基体形态发生，并降低支架蛋白Dlg和α -谱蛋白的突触水平。我们还提供证据表明，Ad与微管切断蛋白Spastin一起作用，分解肌肉中的微管。最后，我们证明了微管不稳定药物长春碱可以减轻atl突变体的突触和肌肉缺陷。总之，我们的研究结果表明，Ad通过调节微管稳定性来控制突触发育、内质网和高尔基体形态发生。(C) 2009爱思唯尔公司版权所有。
Hereditary spastic paraplegia (HSP) is an inherited neurological disorder characterized by progressive spasticity and weakness of the lower extremities. The most common early-onset form of HSP is caused by mutations in the human gene that encodes the dynamin-family GTPase Atlastin-1 (Atl-1). Recently, loss of the Drosophila ortholog of Atl-1 (Atl) has been found to induce locomotor impairments from the earliest adult stages, suggesting the developmental role of atlastin-subfamily GTPases. Here, we provide evidence that Ad is required for normal growth of muscles and synapses at the neuromuscular junction (NMJ). Ad protein is highly expressed in larval body-wall muscles. Loss-of-function mutations in the ad gene reduce the size of muscles and increase the number of synaptic boutons. Rescue of these defects is accomplished by muscular, but not neuronal expression of Ad. Loss of Ad also disrupts ER and Golgi morphogenesis in muscles and reduces the synaptic levels of the scaffold proteins Dlg and alpha-spectrin. We also provide evidence that Ad functions with the microtubule-severing protein Spastin to disassemble microtubules in muscles. Finally, we demonstrate that the microtubule-destabilizing drug vinblastine alleviates synapse and muscle defects in atl mutants. Together, our results suggest that Ad controls synapse development and ER and Golgi morphogenesis by regulating microtubule stability. (C) 2009 Elsevier Inc. All rights reserved.