Differential activation of the ER stress factor XBP1 by oligomeric assemblies

D.L. Castillo-Carranza, Y. Zhang, M.J. Guerrero-Muñoz, R. Kayed, D.E. Rincon-Limas, P. Fernandez-Funez

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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
Pages (from-to)1707-1717
Number of pages11
JournalNeurochemical Research
Volume37
Issue number8
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgments This work was supported by the NIH grant DP2 OD002721-01 to PF-F, start-up funds from the UF Department of Neurology to DER-L and PF-F, and funding from the Mitchell Center for Neurodegenerative Diseases at UTMB for RK.

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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