Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome
Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome
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DOI：
10.1371/journal.pgen.1007363
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发表时间：
2018-04-01
期刊：
影响因子：
4.5
通讯作者：
Bonifacino, Juan S.
中科院分区：
文献类型：
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作者：
De Pace, Raffaella;Skirzewski, Miguel;Bonifacino, Juan S.
遗传性痉挛截瘫(HSP)是一组以进行性肢体痉挛为特征的临床和遗传异质性疾病。异四聚体(epsilon-beta 4-mu4-sigma 4)复合体(AP-4)亚单位的突变导致一种常染色体隐性形式的复杂HSP，称为AP-4缺乏综合征。除肢体痉挛外，该综合征还表现为智力障碍、小头畸形、癫痫发作、穹窿体薄和上肢痉挛。然而，致病机制仍然知之甚少。在这里，我们报告了编码AP-4的epsilon亚单位的AP4E1基因的敲除(KO)小鼠的特征。我们发现AP-4 epsilon KO小鼠表现出一系列的神经学表型，包括后肢紧握、运动协调性降低和握力减弱。此外，AP-4 epsilon KO小鼠在大脑和脊髓的不同区域显示出较薄的胼胝体和轴突肿胀。免疫组织化学分析表明，AP-4的mu4亚基突变患者的皮肤成纤维细胞和AP-4 epsilon KO小鼠的不同神经元类型的皮肤成纤维细胞中，跨膜自噬相关蛋白9A(ATG9A)更多地集中在跨高尔基网络(TGN)中，而在外周细胞质中被耗尽。ATG9A错误定位与AP-4 epsilon KO神经元轴突中积累突变亨廷顿蛋白(HTT)聚集体的倾向增加有关。这些结果表明，AP-4 epsilon KO小鼠是一种适合AP-4缺乏综合征的动物模型，TGN ATG9A动员缺陷和蛋白聚集体自噬降解受损可能是导致这种疾病的神经轴索营养不良的原因。
The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (epsilon-beta 4-mu 4-sigma 4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as "AP-4 deficiency syndrome". In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the epsilon subunit of AP-4. We find that AP-4 epsilon KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 epsilon KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the mu 4 subunit of AP-4 and in various neuronal types in AP-4 epsilon KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 epsilon KO neurons. These findings indicate that the AP-4 epsilon KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.