Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release

Hum Mol Genet. 2001 May 1;10(10):1049-59. doi: 10.1093/hmg/10.10.1049.


Expansion of CAG repeats within the coding region of target genes is the cause of several autosomal dominant neurodegenerative diseases including Huntington's disease (HD). A hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD. Proteasomal 20S core catalytic component was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components from the total cellular environment to the aggregates, as well as the comparatively slower degradation of tNhtt with longer polyglutamine, decreased the proteasome's availability for degrading other key target proteins, such as p53. This altered proteasomal function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol and activated caspase-9- and caspase-3-like proteases. These results suggest that the impaired proteasomal function plays an important role in polyglutamine protein-induced cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspases / biosynthesis*
  • Cell Line
  • Cysteine Endopeptidases / metabolism*
  • Cytochrome c Group / metabolism*
  • Endopeptidases / genetics
  • Endopeptidases / metabolism
  • Endopeptidases / physiology
  • Enzyme Activation
  • Humans
  • Huntingtin Protein
  • Huntington Disease / enzymology
  • Huntington Disease / etiology*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Immunoblotting
  • Mice
  • Mice, Transgenic
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Mitochondria / ultrastructure
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Peptide Fragments
  • Peptides / genetics
  • Peptides / metabolism*
  • Proteasome Endopeptidase Complex
  • Repetitive Sequences, Nucleic Acid
  • Ubiquitins / metabolism


  • Cytochrome c Group
  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptide Fragments
  • Peptides
  • Ubiquitins
  • polyglutamine
  • Endopeptidases
  • Caspases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex