Differential activation of the ER stress factor XBP1 by oligomeric assemblies

Diana L. Castillo-Carranza, Yan Zhang, Marcos J. Guerrero-Muñoz, Rakez Kayed, Diego E. Rincon-Limas, Pedro Fernandez-Funez

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Several neurodegenerative disorders are characterized by protein misfolding, a phenomenon that results in perturbation of cellular homeostasis. We recently identified the protective activity of the ER stress response factor XBP1 (X-box binding protein 1) against Amyloid-ß1-42 (Aß42) neurotoxicity in cellular and Drosophila models of Alzheimer's disease. Additionally, subtoxic concentrations of Aß42 soluble aggregates (oligomers) induced accumulation of spliced (active) XBP1 transcripts, supporting the involvement of the ER stress response in Aß42 neurotoxicity. Here, we tested the ability of three additional diseaserelated amyloidogenic proteins to induce ER stress by analyzing XBP1 activation at the RNA level. Treatment of human SY5Y neuroblastoma cells with homogeneous preparations of α-Synuclein (α-Syn), Prion protein (PrP106-126), and British dementia amyloid peptide (ABri1-34) confirmed the high toxicity of oligomers compared to monomers and fibers. Additionally, α-Syn oligomers, but not monomers or fibers, demonstrated potent induction of XBP1 splicing. On the other hand, PrP106-126 and ABri1-34 did not activate XBP1. These results illustrate the biological complexity of these structurally related assemblies and argue that oligomer toxicity depends on the activation of amyloid-specific cellular responses.

Original languageEnglish (US)
Pages (from-to)1707-1717
Number of pages11
JournalNeurochemical Research
Volume37
Issue number8
DOIs
StatePublished - Aug 2012

Keywords

  • Amyloids
  • ER stress
  • Neurodegeneration
  • Oligomers
  • XBP1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry

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  • Cite this

    Castillo-Carranza, D. L., Zhang, Y., Guerrero-Muñoz, M. J., Kayed, R., Rincon-Limas, D. E., & Fernandez-Funez, P. (2012). Differential activation of the ER stress factor XBP1 by oligomeric assemblies. Neurochemical Research, 37(8), 1707-1717. https://doi.org/10.1007/s11064-012-0780-7