Oxysterol-binding protein ORP3 rescues the Amyotrophic Lateral Sclerosis-linked mutant VAPB phenotype

Exp Cell Res. 2016 Feb 1;341(1):18-31. doi: 10.1016/j.yexcr.2016.01.013. Epub 2016 Jan 23.


A mutation in VAPB causes a familial form of Amyotrophic Lateral Sclerosis. The mutant protein (VAPB-P56S) is aggregate prone and blocks retrograde traffic from the endoplasmic reticulum (ER) Golgi intermediate compartment (ERGIC) including trafficking to the nuclear envelope (NE). Here we report a morphological screen where overexpression of oxysterol binding protein-related protein-3 (ORP3) rescued the mutant VAPB phenotype. It resolved the mutant VAPB-induced membrane expansions, restored solubility of the mutant protein in non-ionic detergent, and restored trafficking of Emerin to the NE. Knockdown of ORP3 or VAPB increased the intracellular level of phosphatidylinositol 4-phosphate (PtdIns4P). Decreasing PtdIns4P levels by inhibiting its synthesis reduced the severity of the mutant VAPB-induced membrane expansions and restored Emerin trafficking to the NE. Thus, VAPB and its interacting partners cooperatively regulate protein trafficking through the ERGIC by modulating PtdIns4P levels.

Keywords: Amyotrophic Lateral Sclerosis; Endoplasmic reticulum Golgi intermediate compartment (ERGIC); Nuclear envelope; Oxysterol binding protein-related protein; Phosphatidylinositol 4-phosphate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Carrier Proteins / metabolism*
  • Fatty Acid-Binding Proteins
  • HeLa Cells
  • Humans
  • Phenotype*
  • Tumor Cells, Cultured
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism


  • Carrier Proteins
  • Fatty Acid-Binding Proteins
  • OSBPL3 protein, human
  • VAPB protein, human
  • Vesicular Transport Proteins