A disease causing ATLASTIN 3 mutation affects multiple endoplasmic reticulum-related pathways
A disease causing ATLASTIN 3 mutation affects multiple endoplasmic reticulum-related pathways
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DOI：
10.1007/s00018-019-03010-x
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发表时间：
2019-04-01
影响因子：
8
通讯作者：
Kaether, Christoph
中科院分区：
文献类型：
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作者：
Behrendt, Laura;Kurth, Ingo;Kaether, Christoph
Atlastins（ATLs）是参与内质网（ER）形成的膜结合GTP酶。ATL1和ATL3的突变导致痉挛性截瘫和遗传性感觉神经病。我们在这里表明，感觉神经病变引起的ATL 3 Y192C突变降低了管状ER网络的复杂性。ATL3 Y192C通过减少ER出口位点的数量来延迟ER出口，减少自噬，使高尔基体碎片化并导致核畸形。在培养的原代神经元中，ATL 3 Y192C不定位于生长的轴突，导致轴突生长缺陷。患者来源的成纤维细胞具有复杂性降低的管状ER，并且具有减少数量的自噬体。这些数据表明，导致疾病的ATL 3 Y192C突变影响多种ER相关通路，可能是由于ER形态扭曲的结果。
Atlastins (ATLs) are membrane-bound GTPases involved in shaping of the endoplasmic reticulum (ER). Mutations in ATL1 and ATL3 cause spastic paraplegia and hereditary sensory neuropathy. We here show that the sensory neuropathy causing ATL3 Y192C mutation reduces the complexity of the tubular ER-network. ATL3 Y192C delays ER-export by reducing the number of ER exit sites, reduces autophagy, fragments the Golgi and causes malformation of the nucleus. In cultured primary neurons, ATL3 Y192C does not localize to the growing axon, resulting in axon growth deficits. Patient-derived fibroblasts possess a tubular ER with reduced complexity and have a reduced number of autophagosomes. The data suggest that the disease-causing ATL3 Y192C mutation affects multiple ER-related pathways, possibly as a consequence of the distorted ER morphology.