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The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control

Amina Moustaqim-Barrette1, Yong Q Lin, Sreeparna Pradhan

  • 1Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4 Canada.

Human Molecular Genetics
|November 26, 2013
PubMed

Insights

Amyotrophic lateral sclerosis (ALS8) is linked to VapB mutations, impacting ER protein quality control. Restoring Osbp function in the ER rescues these defects, suggesting a key role in ALS8 pathology.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease.
  • Familial ALS (ALS8) is associated with mutations in the VapB gene.
  • VapB is a transmembrane protein localized to the endoplasmic reticulum (ER).

Purpose of the Study:

  • To investigate the role of VapB in ER protein quality control (ERQC).
  • To understand the consequences of the ALS8-associated VapB mutation (P56S) in the ER.
  • To elucidate the molecular mechanisms underlying ALS8 pathogenesis.

Main Methods:

  • Utilized Drosophila melanogaster as a model organism.
  • Assessed ERQC defects, including protein accumulation and ER stress.
  • Investigated protein-protein interactions between VapB and Osbp using biochemical assays.
  • Examined the localization of Osbp in the ER.

Main Results:

  • Loss of Vap in flies leads to ERQC defects like protein accumulation and ER stress.
  • Wild-type Vap, but not the ALS8 mutant Vap, interacts with Oxysterol binding protein (Osbp).
  • Vap is essential for the correct ER localization of Osbp.
  • Restoring Osbp expression in the ER rescues Vap loss- and ALS8 mutant Vap-associated defects.

Conclusions:

  • Vap is crucial for ER protein quality control.
  • The ALS8 mutation in VapB disrupts its interaction with Osbp.
  • Impaired VapB-Osbp interaction leads to ER dysfunction and contributes to ALS8 pathology.

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