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Sensory-neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering

(2018) CELL REPORTS. 23(7). p. 2026-2038
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Organization
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.
Keywords
ENDOPLASMIC-RETICULUM MEMBRANES, HEREDITARY SPASTIC PARAPLEGIA, GTPASE ATLASTIN, HOMOTYPIC FUSION, STRUCTURAL BASIS, IMAGE-ANALYSIS, NETWORK, MORPHOGENESIS, DIMERIZATION, HYDROLYSIS

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Citation

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Chicago
Krols, Michiel, Sammy Detry, Bob Asselbergh, Leonardo Almeida-Souza, Anna Kremer, Saskia Lippens, Riet De Rycke, et al. 2018. “Sensory-neuropathy-causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering.” Cell Reports 23 (7): 2026–2038.
APA
Krols, Michiel, Detry, S., Asselbergh, B., Almeida-Souza, L., Kremer, A., Lippens, S., De Rycke, R., et al. (2018). Sensory-neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering. CELL REPORTS, 23(7), 2026–2038.
Vancouver
1.
Krols M, Detry S, Asselbergh B, Almeida-Souza L, Kremer A, Lippens S, et al. Sensory-neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering. CELL REPORTS. 2018;23(7): 2026–38.
MLA
Krols, Michiel, Sammy Detry, Bob Asselbergh, et al. “Sensory-neuropathy-causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering.” CELL REPORTS 23.7 (2018): 2026–2038. Print.
@article{8565007,
  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.},
  author       = {Krols, Michiel and Detry, Sammy and Asselbergh, Bob and Almeida-Souza, Leonardo and Kremer, Anna and Lippens, Saskia and De Rycke, Riet and De Winter, Vicky and M{\"u}ller, Franz-Josef and Kurth, Ingo and McMahon, Harvey T and Savvides, Savvas and Timmerman, Vincent and Janssens, Sophie},
  issn         = {2211-1247},
  journal      = {CELL REPORTS},
  language     = {eng},
  number       = {7},
  pages        = { 2026--2038},
  title        = {Sensory-neuropathy-causing mutations in ATL3 cause aberrant ER membrane tethering},
  url          = {http://dx.doi.org/10.1016/j.celrep.2018.04.071},
  volume       = {23},
  year         = {2018},
}

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