Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease.
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.
Hoffner
Guylaine
G
CNRS --- UPR 2228, Régulation de la Transcription et Maladies Génétiques, Université René Descartes, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
Kahlem
Pascal
P
Djian
Philippe
P
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002451:Cell Compartmentation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D014404:Tubulin; C097188:polyglutamine