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FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation

Derek C Prosser1, Duvinh Tran, Pierre-Yves Gougeon

  • 1Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, K1Y 4E9 Canada.

Journal of Cell Science
|August 21, 2008
PubMed

Insights

VAMP-associated proteins (VAP) regulate ER-to-Golgi transport. Overexpression of VAP isoforms impedes membrane protein movement and vesicle formation, potentially causing disease, but FFAT motif expression can restore normal function.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • VAMP-associated proteins (VAP) are key regulators of intracellular transport.
  • A specific mutation in VAPB (VAMP-associated protein B) is linked to amyotrophic lateral sclerosis (ALS8).
  • VAP proteins possess an N-terminal major sperm protein (MSP) domain involved in protein interactions.

Purpose of the Study:

  • To investigate the role of VAP isoforms (VAPA and VAPB) in ER-to-Golgi transport.
  • To elucidate the mechanism by which VAP overexpression affects membrane protein trafficking.
  • To explore the therapeutic potential of the FFAT motif in VAP-related cellular dysfunction.

Main Methods:

  • Overexpression of VAPA and VAPB in cellular models.
  • Analysis of ER-to-Golgi transport of membrane proteins.
  • Investigation of protein lateral diffusion and ER vesicle budding.
  • Utilizing FFAT motif peptides to counteract VAP effects.

Main Results:

  • VAPA overexpression inhibits ER-to-Golgi transport by reducing cargo segregation into ER vesicles.
  • VAPA impedes membrane protein lateral diffusion through microtubule association.
  • Overexpression of the FFAT motif rescues ER-to-Golgi transport, normalizes diffusion, and resolves ER aggregates caused by VAPB-P56S.
  • FFAT peptide application restores in vitro ER vesicle budding and disrupts VAP-microtubule interactions.

Conclusions:

  • VAP isoforms play a critical role in regulating membrane protein trafficking and lateral diffusion.
  • VAP overexpression leads to ER retention of membrane proteins by hindering vesicle formation.
  • The FFAT motif represents a potential therapeutic target for VAP-mediated cellular defects and ALS8.

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