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

J Neurochem. 2003 Jul;86(2):394-404. doi: 10.1046/j.1471-4159.2003.01844.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Canavanine / pharmacology
  • Cell Survival / drug effects
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Green Fluorescent Proteins
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Molecular Chaperones / biosynthesis*
  • Molecular Chaperones / genetics
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Peptide Hydrolases / drug effects
  • Peptide Hydrolases / metabolism*
  • Proteasome Endopeptidase Complex*
  • RNA, Messenger / metabolism
  • Transfection
  • Transgenes
  • Tumor Cells, Cultured
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*
  • Ubiquitin / pharmacology

Substances

  • Enzyme Inhibitors
  • Heat-Shock Proteins
  • Luminescent Proteins
  • Molecular Chaperones
  • RNA, Messenger
  • Ubiquitin
  • Green Fluorescent Proteins
  • Canavanine
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease