Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering

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. [Display omitted] •HSAN-causing ATL3 mutants are less fusogenic but retain their dimerization capacity•Recombinant mutant ATL3 proteins cause excessive liposome tethering•In cells, HSAN-causing ATL3 mutants lead to collapse of the ER•Volume EM revealed that ER collapse is hallmarked by laterally tethered ER tubules Mutations in atlastins (ATLs), the ER fusion proteins in mammals, cause neurodegeneration. Using volume EM in patient fibroblasts, Krols et al. reveal that HSAN-causing mutations in ATL3 promote aberrant ER tethering due to a defect in an intermediate step in the functional cycle of the ATL3 GTPase.