Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression

Andrew D Hope, Rohan de Silva, David F Fischer, Elly M Hol, Fred W van Leeuwen, Andrew J Lees

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Intracellular protein inclusions in Alzheimer's disease and progressive supranuclear palsy contain UBB+1, a variant ubiquitin. UBB+1 is able block the 26S proteasome in cell lines. Proteasome inhibition by drug action has previously been shown to induce a heat-shock response and render protection against stress. We investigated UBB+1 by developing a stable, conditional expression model in SH-SY5Y human neuroblastoma cells. Induction of UBB+1 expression caused proteasome inhibition as was confirmed by reduced ability to process misfolded canavanyl proteins, accumulation of GFPu, a proteasome substrate, and reduced cleavage of a fluorogenic substrate. We show that expression of UBB+1 induces expression of heat-shock proteins. This priming of the chaperone system in these cells promotes a subsequent resistance to tert-butyl hydroperoxide-mediated oxidative stress. We conclude that although UBB+1-expressing cells have a compromised ubiquitin-proteasome system, they are protected against oxidative stress conditions.

Original languageEnglish
Pages (from-to)394-404
Number of pages11
JournalJournal of Neurochemistry
Volume86
Issue number2
Publication statusPublished - Jul 2003

Keywords

  • Alzheimer Disease
  • Canavanine
  • Cell Survival
  • Enzyme Inhibitors
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Heat-Shock Proteins
  • Humans
  • Luminescent Proteins
  • Molecular Chaperones
  • Neuroblastoma
  • Oxidative Stress
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • RNA, Messenger
  • Transfection
  • Transgenes
  • Tumor Cells, Cultured
  • Ubiquitin
  • Journal Article
  • Research Support, Non-U.S. Gov't

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