Publication
Title
Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering
Author
Abstract
The endoplasmic reticulum (ER) is a complex network of sheets and tubules that is continuously remodeled. The relevance of this membrane dynamics is underscored by the fact that mutations in atlastins (ATLs), the ER fusion proteins in mammals, cause neurodegeneration. How defects in this process disrupt neuronal homeostasis is unclear. Using electron microscopy (EM) volume reconstruction of transfected cells, neurons, and patient fibroblasts, we show that hereditary sensory and autonomic neuropathy (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 in an intermediate step of the ATL3 functional cycle. Our data show that the effects of ATL3 mutations on ER network organization go beyond a loss of fusion and shed light on neuropathies caused by atlastin defects.
Language
English
Source (journal)
Cell reports
Publication
2018
ISSN
2211-1247
Volume/pages
23 :7 (2018) , p. 2026-2038
ISI
000432455600012
Pubmed ID
29768202
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
VIB-Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS).
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 10.07.2018
Last edited 20.09.2021
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