A disease causing ATLASTIN 3 mutation affects multiple endoplasmic reticulum-related pathways

Cell Mol Life Sci. 2019 Apr;76(7):1433-1445. doi: 10.1007/s00018-019-03010-x. Epub 2019 Jan 21.

Abstract

Atlastins (ATLs) are membrane-bound GTPases involved in shaping of the endoplasmic reticulum (ER). Mutations in ATL1 and ATL3 cause spastic paraplegia and hereditary sensory neuropathy. We here show that the sensory neuropathy causing ATL3 Y192C mutation reduces the complexity of the tubular ER-network. ATL3 Y192C delays ER-export by reducing the number of ER exit sites, reduces autophagy, fragments the Golgi and causes malformation of the nucleus. In cultured primary neurons, ATL3 Y192C does not localize to the growing axon, resulting in axon growth deficits. Patient-derived fibroblasts possess a tubular ER with reduced complexity and have a reduced number of autophagosomes. The data suggest that the disease-causing ATL3 Y192C mutation affects multiple ER-related pathways, possibly as a consequence of the distorted ER morphology.

Keywords: Atlastin; Endoplasmic reticulum; Hereditary spastic paraplegia; Secretory transport.

MeSH terms

  • Animals
  • Autophagosomes
  • Autophagy
  • Axons / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / pathology
  • HeLa Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / metabolism

Substances

  • Membrane Proteins
  • ATL1 protein, human
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • ATL3 protein, human