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

Angie Darbyson1, Johnny K Ngsee1

  • 1Ottawa Hospital Research Institute Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.

Experimental Cell Research
|January 27, 2016
PubMed

Insights

Oxysterol binding protein-related protein-3 (ORP3) can rescue a familial form of Amyotrophic Lateral Sclerosis (ALS) caused by mutant VAPB. ORP3 and phosphatidylinositol 4-phosphate (PtdIns4P) levels regulate protein trafficking.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • A mutation in VAMP-associated protein B (VAPB) causes familial Amyotrophic Lateral Sclerosis (ALS).
  • Mutant VAPB (VAPB-P56S) forms aggregates and disrupts retrograde protein transport from the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) to the nuclear envelope (NE).

Purpose of the Study:

  • To identify factors that rescue the cellular defects caused by mutant VAPB.
  • To elucidate the role of VAPB and its interacting partners in protein trafficking regulation.

Main Methods:

  • Morphological screening of genetic modifiers.
  • Assessing protein solubility and subcellular localization.
  • Investigating the role of phosphatidylinositol 4-phosphate (PtdIns4P) in VAPB-related cellular dysfunction.

Main Results:

  • Overexpression of oxysterol binding protein-related protein-3 (ORP3) rescued VAPB-P56S-induced membrane expansions and restored Emerin trafficking to the NE.
  • ORP3 overexpression restored the solubility of VAPB-P56S.
  • Knockdown of ORP3 or VAPB increased intracellular PtdIns4P levels, and decreasing PtdIns4P ameliorated VAPB-P56S phenotypes.

Conclusions:

  • VAPB and interacting proteins, like ORP3, regulate protein trafficking via the ERGIC.
  • Modulation of PtdIns4P levels is a key mechanism in VAPB-mediated protein transport.
  • ORP3 is a potential therapeutic target for VAPB-related ALS.
Keywords:
Amyotrophic Lateral SclerosisEndoplasmic reticulum Golgi intermediate compartment (ERGIC)Nuclear envelopeOxysterol binding protein-related proteinPhosphatidylinositol 4-phosphate

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