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

Cathal Wilson1, Rossella Venditti2, Maria Antonietta De Matteis2

  • 1Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

Advances in Biological Regulation
|January 19, 2021
PubMed

Insights

Amyotrophic lateral sclerosis 8 (ALS8) involves motor neuron death due to VAPB mutations affecting cellular lipid exchange. Increased phosphatidylinositol-4-phosphate (PI4P) is a key feature, potentially offering a therapeutic target for ALS8.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Amyotrophic lateral sclerosis 8 (ALS8) is a neurodegenerative disease characterized by motor neuron loss.
  • ALS8 pathogenesis is linked to mutations in the Vesicle-Associated Membrane Protein-Associated Protein B (VAPB).
  • VAPB functions at membrane contact sites, regulating organelle communication and lipid exchange.

Purpose of the Study:

  • To investigate the role of phosphatidylinositol-4-phosphate (PI4P) deregulation in ALS8.
  • To explore PI4P as a potential therapeutic target for ALS8.

Main Methods:

  • Analysis of VAPB mutations and their impact on cellular functions.
  • Investigation of lipid metabolism, specifically PI4P levels, in ALS8 models.
  • Assessment of VAPB's role at endoplasmic reticulum (ER)-organelle contact sites.

Main Results:

  • Mutations in VAPB lead to significant increases in cellular PI4P levels.
  • VAPB's function in lipid exchange at membrane contact sites is crucial.
  • PI4P deregulation is a recurrent phenotype in VAPB-deficient models.

Conclusions:

  • Dysregulation of PI4P is implicated in the development of ALS8.
  • Targeting PI4P pathways may offer a novel therapeutic strategy for ALS8.
Keywords:
Amyotrophic lateral sclerosis 8Membrane contact sitesPhosphatidylinositol-4-phosphateVAPB

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