Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease

J Cell Sci. 2002 Mar 1;115(Pt 5):941-8.

Abstract

Huntington's disease results from an expansion of a series of glutamine repeats in the protein huntingtin. We have discovered from immunopurification studies that huntingtin combines specifically with the beta subunit of tubulin. This binding explains why huntingtin can be shown on assembled microtubules by electron microscopy. Immunostaining shows that most of the huntingtin in the cytoplasm is associated with microtubules. Huntingtin is particularly abundant in the perinuclear region, where it is also associated with microtubules and in the centrosomal region, where it co-localizes with gamma-tubulin. In Huntington's disease, inclusions are often nuclear or perinuclear. Since the perinuclear concentration of huntingtin does not depend on the number of its glutamine repeats, we propose that inclusions are found in perinuclear and intranuclear locations because the beta-tubulin binding property of huntingtin brings it to the perinuclear region, from which it readily gains access to the nucleus. The mutational glutamine expansion then promotes insolubility and results in an inclusion.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Brain / physiopathology
  • Cell Compartmentation / physiology
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Centrosome / metabolism
  • Centrosome / ultrastructure
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Microtubules / metabolism*
  • Microtubules / pathology
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Neurons / pathology
  • Nuclear Proteins / metabolism*
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Binding / physiology
  • Rats
  • Trinucleotide Repeat Expansion / genetics
  • Tubulin / metabolism*
  • Tumor Cells, Cultured

Substances

  • HTT protein, human
  • Htt protein, rat
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Tubulin
  • polyglutamine