Deregulation of phosphatidylinositol-4-phosphate in the development of amyotrophic lateral sclerosis 8

Adv Biol Regul. 2021 Jan:79:100779. doi: 10.1016/j.jbior.2020.100779. Epub 2020 Dec 29.

Abstract

Amyotrophic lateral sclerosis 8 (ALS8) is one of a heterogeneous group of progressive neurodegenerative disorders characterized by the death of motor neurons. ALS8 is caused by mutations in VAPB, a protein that acts at multiple membrane contact sites between the endoplasmic reticulum (ER) and almost all other organelles and thus affects functions at diverse cellular locations. One prominent function mediated by VAPB at these sites is lipid exchange, and a recurrent phenotype observed in all models investigating knockout or knockdown of VAPs is a significant increase in the levels of phosphatidylinositol-4-phosphate (PI4P). Here we consider the relevance of this PI4P deregulation in the development of ALS8 that might represent a potential target for therapeutic intervention.

Keywords: Amyotrophic lateral sclerosis 8; Membrane contact sites; Phosphatidylinositol-4-phosphate; VAPB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Motor Neurons / metabolism
  • Mutation
  • Phenotype
  • Phosphatidylinositol Phosphates / metabolism*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism

Substances

  • Phosphatidylinositol Phosphates
  • VAPB protein, human
  • Vesicular Transport Proteins
  • phosphatidylinositol 4-phosphate

Supplementary concepts

  • Amyotrophic Lateral Sclerosis 8