Inefficient degradation of truncated polyglutamine proteins by the proteasome

Carina I. Holmberg, Kristine E. Staniszewski, Kwame N. Mensah, Andreas Matouschek, Richard I. Morimoto*

*Corresponding author for this work

Research output: Contribution to journalArticle

215 Scopus citations

Abstract

Accumulation of mutant proteins into misfolded species and aggregates is characteristic for diverse neurodegenerative diseases including the polyglutamine diseases. While several studies have suggested that polyglutamine protein aggregates impair the ubiquitin-proteasome system, the molecular mechanisms underlying the interaction between polyglutamine proteins and the proteasome have remained elusive. In this study, we use fluorescence live-cell imaging to demonstrate that the proteasome is sequestered irreversibly within aggregates of overexpressed N-terminal mutant Huntingtin fragment or simple polyglutamine expansion proteins. Moreover, by direct targeting of polyglutamine proteins for proteasomal degradation, we observe incomplete degradation of these substrates both in vitro and in vivo. Thus, our data reveal that intrinsic properties of the polyglutamine proteins prevent their efficient degradation and clearance. Additionally, fluorescence resonance energy transfer is detected between the proteasome and aggregated polyglutamine proteins indicative of a close and stable interaction. We propose that polyglutamine-containing proteins are kinetically trapped within proteasomes, which could explain their deleterious effects on cellular function over time.

Original languageEnglish (US)
Pages (from-to)4307-4318
Number of pages12
JournalEMBO Journal
Volume23
Issue number21
DOIs
StatePublished - Oct 27 2004

Keywords

  • FLIP
  • FRAP
  • FRET
  • Polyglutamine proteins
  • Proteasome

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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