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Differential activation of the ER stress factor XBP1 by oligomeric assemblies

Diana L Castillo-Carranza1, Yan Zhang, Marcos J Guerrero-Muñoz

  • 1Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA.

Neurochemical Research
|April 25, 2012
PubMed

Insights

Alpha-synuclein oligomers activate the ER stress response, unlike prion or British dementia peptides. This highlights amyloid-specific cellular responses in neurodegenerative disease pathogenesis.

Area of Science:

  • Neurobiology
  • Molecular Biology
  • Cellular Biology

Background:

  • Protein misfolding and ER stress are hallmarks of neurodegenerative diseases.
  • X-box binding protein 1 (XBP1) is an ER stress response factor.
  • Amyloid-ß1-42 (Aß42) oligomers induce XBP1 activation in Alzheimer's disease models.

Purpose of the Study:

  • To investigate the ER stress-inducing potential of other amyloidogenic proteins.
  • To analyze XBP1 activation by alpha-synuclein (α-Syn), prion protein (PrP106-126), and British dementia amyloid peptide (ABri1-34).

Main Methods:

  • Treatment of human SY5Y neuroblastoma cells with purified protein preparations (monomers, oligomers, fibers).
  • Analysis of XBP1 splicing (activation) at the RNA level.
  • Assessment of protein aggregate toxicity.

Main Results:

  • Oligomers of α-Syn, PrP106-126, and ABri1-34 were more toxic than monomers or fibers.
  • α-Syn oligomers potently induced XBP1 splicing.
  • PrP106-126 and ABri1-34 did not activate XBP1 splicing.

Conclusions:

  • Oligomer toxicity is dependent on amyloid-specific cellular responses.
  • The ER stress response activation varies among different amyloidogenic proteins.
  • This study reveals the complexity of protein misfolding in neurodegeneration.

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