Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice

Neuron. 1999 Dec;24(4):879-92. doi: 10.1016/s0896-6273(00)81035-1.

Abstract

Mutant ataxin-1, the expanded polyglutamine protein causing spinocerebellar ataxia type 1 (SCA1), aggregates in ubiquitin-positive nuclear inclusions (NI) that alter proteasome distribution in affected SCA1 patient neurons. Here, we observed that ataxin-1 is degraded by the ubiquitin-proteasome pathway. While ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquitinated equally well in vitro, the mutant form is three times more resistant to degradation. Inhibiting proteasomal degradation promotes ataxin-1 aggregation in transfected cells. And in mice, Purkinje cells that express mutant ataxin-1 but not a ubiquitin-protein ligase have significantly fewer NIs. Nonetheless, the Purkinje cell pathology is markedly worse than that of SCA1 mice. Taken together, NIs are not necessary to induce neurodegeneration, but impaired proteasomal degradation of mutant ataxin-1 may contribute to SCA1 pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ataxin-1
  • Ataxins
  • Cell Nucleus / genetics*
  • Cell Nucleus / pathology
  • Cells, Cultured
  • Cysteine Endopeptidases / metabolism
  • Fluorescent Antibody Technique
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Inclusion Bodies / genetics*
  • Inclusion Bodies / pathology
  • Ligases / deficiency
  • Ligases / genetics*
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Multienzyme Complexes / metabolism
  • Mutation / physiology
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics*
  • Peptides / toxicity*
  • Phenotype
  • Plasmids / genetics
  • Proteasome Endopeptidase Complex
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Purkinje Cells / ultrastructure
  • Spinocerebellar Degenerations / genetics*
  • Spinocerebellar Degenerations / pathology
  • Ubiquitin-Protein Ligases
  • Ubiquitins / genetics
  • Ubiquitins / metabolism

Substances

  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Ubiquitins
  • polyglutamine
  • Ubiquitin-Protein Ligases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Ligases