Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias

Nature. 1995 Nov 23;378(6555):403-6. doi: 10.1038/378403a0.

Abstract

A polyglutamine expansion (encoded by a CAG repeat) in specific proteins causes neurodegeneration in Huntington's disease (HD) and four other disorders, by an unknown mechanism thought to involve gain of function or toxicity of the mutated protein. The pathological threshold is 37-40 glutamines in three of these diseases, whereas the corresponding normal proteins contain polymorphic repeats of up to about 35 glutamines. The age of onset of clinical manifestations is inversely correlated to the length of the polyglutamine expansion. Here we report the characterization of a monoclonal antibody that selectively recognizes polyglutamine expansion in the proteins implicated in HD and in spinocerebellar ataxia (SCA) 1 and 3. The intensity of signal depends on the length of the polyglutamine expansion, and the antibody also detects specific pathological proteins expected to contain such expansion, in SCA2 and in autosomal dominant cerebellar ataxia with retinal degeneration, whose genes have not yet been identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal / immunology
  • Ataxin-1
  • Ataxins
  • Blotting, Western
  • Cell Line
  • Cerebellar Ataxia / immunology
  • Cerebellar Ataxia / metabolism*
  • Cerebellar Ataxia / pathology
  • DNA-Binding Proteins / metabolism
  • Female
  • Glutamine / immunology
  • Glutamine / metabolism*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / immunology
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Male
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / immunology
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism*
  • TATA-Box Binding Protein
  • Transcription Factors / metabolism

Substances

  • ATXN1 protein, human
  • Antibodies, Monoclonal
  • Ataxin-1
  • Ataxins
  • DNA-Binding Proteins
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • TATA-Box Binding Protein
  • Transcription Factors
  • Glutamine