Disease-causing mutated ATLASTIN 3 is excluded from distal axons and reduces axonal autophagy

NEUROBIOLOGY OF DISEASE

卷:155

Article

Behrendt, Laura¹  Hoischen, Christian¹  Kaether, Christoph¹ 

[1] Fritz Lipmann Inst, Leibniz Inst Alternsforsch, Beutenbergstr 11, D-07745 Jena, Germany

关键词: Atlastin;    Axonopathy;    Hereditary sensory neuropathy;    Endoplasmic reticulum;    Autophagy;   

DOI  :  10.1016/j.nbd.2021.105400

来源: Elsevier

【 摘 要 】

Mutations in the ER-network forming GTPase atlastin3 (ATL3) can cause axon degeneration of sensory neurons by not fully understood mechanisms. We here show that the hereditary sensory and autonomous neuropathy (HSAN)-causing ATL3 Y192C or P338R are excluded from distal axons by a barrier at the axon initial segment (AIS). This barrier is selective for mutated ATL3, but not wildtype ATL3 or unrelated ER-membrane proteins. Actin-depolymerization partially restores the transport of ATL3 Y192C into distal axons. The results point to the existence of a selective diffusion barrier in the ER membrane at the AIS, analogous to the AIS-based barriers for plasma membrane and cytosolic proteins. Functionally, the absence of ATL3 at the distal axon reduces axonal autophagy and the ER network deformation in the soma causes a reduction in axonal lysosomes. Both could contribute to axonal degeneration and eventually to HSAN.