Dose-dependent inhibition of proteasome activity by a mutant ubiquitin associated with neurodegenerative disease

Paula van Tijn, Femke M S de Vrij, Karianne G Schuurman, Nico P Dantuma, David F Fischer, Fred W van Leeuwen, Elly M Hol

Research output: Contribution to journalArticleAcademicpeer-review


The ubiquitin-proteasome system is the main regulated intracellular proteolytic pathway. Increasing evidence implicates impairment of this system in the pathogenesis of diseases with ubiquitin-positive pathology. A mutant ubiquitin, UBB(+1), accumulates in the pathological hallmarks of tauopathies, including Alzheimer's disease, polyglutamine diseases, liver disease and muscle disease and serves as an endogenous reporter for proteasomal dysfunction in these diseases. UBB(+1) is a substrate for proteasomal degradation, however it can also inhibit the proteasome. Here, we show that UBB(+1) properties shift from substrate to inhibitor in a dose-dependent manner in cell culture using an inducible UBB(+1) expression system. At low expression levels, UBB(+1) was efficiently degraded by the proteasome. At high levels, the proteasome failed to degrade UBB(+1), causing its accumulation, which subsequently induced a reversible functional impairment of the ubiquitin-proteasome system. Also in brain slice cultures, UBB(+1) accumulation and concomitant proteasome inhibition was only induced at high expression levels. Our findings show that by varying UBB(+1) expression levels, the dual proteasome substrate and inhibitory properties can be optimally used to serve as a research tool to study the ubiquitin-proteasome system and to further elucidate the role of aberrations of this pathway in disease.

Original languageEnglish
Pages (from-to)1615-23
Number of pages9
JournalJournal of Cell Science
Issue numberPt 9
Publication statusPublished - 2007


  • Animals
  • Blotting, Western
  • Cerebral Cortex
  • Cysteine Proteinase Inhibitors
  • Cytosol
  • Dose-Response Relationship, Drug
  • Doxorubicin
  • Flow Cytometry
  • Frameshift Mutation
  • Gene Expression
  • Green Fluorescent Proteins
  • HeLa Cells
  • Humans
  • Leupeptins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Neurodegenerative Diseases
  • Oligopeptides
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors
  • Tissue Culture Techniques
  • Transfection
  • Ubiquitin
  • Journal Article
  • Research Support, Non-U.S. Gov't


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