Sensory neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering
Sensory neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering
SUMMARY The ER is a complex network of sheets and tubules that is continuously being remodeled. The relevance of this membrane dynamics is underscored by the fact that mutations in Atlastins (ATL), the ER fusion proteins in mammals, cause neurodegeneration. How defects in this process disrupt neuronal homeostasis is largely unknown. Here we show by EM volume reconstruction of transfected cells, neurons and patient fibroblasts that the HSAN-causing ATL3 mutants promote aberrant ER tethering hallmarked by bundles of laterally attached ER tubules. In vitro, these mutants cause excessive liposome tethering, recapitulating the results in cells. Moreover, ATL3 variants retain their dimerization-dependent GTPase activity, but are unable to promote membrane fusion, suggesting a defect on an intermediate step of the ATL3 functional cycle. Our data therefore show that the effects of ATL3 mutations on ER network organization stretch beyond a loss of fusion, shedding a new light on neuropathies caused by atlastin defects.
Krols Michiel、Janssens Sophie、Rycke Riet de、M¨1ller Franz-Josef、Winter Vicky De、McMahon Harvey T.、Detry Sammy、Kremer Anna、Timmerman Vincent、Kurth Ingo、Lippens Saskia、Almeida-Souza Leonardo、Asselbergh Bob、Savvides Savvas N.
Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp||Institute Born BungeLaboratory of ER stress and Inflammation, VIB Center for Inflammation Research, Ghent University||Department of Internal Medicine, Ghent UniversityVIB BioImaging Core||Department of Biomedical Molecular Biology, Ghent UniversityZentrum f¨1r Integrative PsychiatriePeripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp||Institute Born BungeMRC Laboratory of Molecular BiologyUnit for Structural Biology, VIB Center for Inflammation Research, Ghent University||Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent UniversityVIB BioImaging Core||Department of Biomedical Molecular Biology, Ghent UniversityPeripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp||Institute Born BungeInstitute of Human Genetics, Medical Faculty, RWTH Aachen UniversityVIB BioImaging Core||Department of Biomedical Molecular Biology, Ghent UniversityMRC Laboratory of Molecular BiologyVIB-UAntwerp Center for Molecular Neurology, University of AntwerpUnit for Structural Biology, VIB Center for Inflammation Research, Ghent University||Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University
基础医学神经病学、精神病学细胞生物学
Krols Michiel,Janssens Sophie,Rycke Riet de,M¨1ller Franz-Josef,Winter Vicky De,McMahon Harvey T.,Detry Sammy,Kremer Anna,Timmerman Vincent,Kurth Ingo,Lippens Saskia,Almeida-Souza Leonardo,Asselbergh Bob,Savvides Savvas N..Sensory neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/192484.点此复制
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