Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix

Hum Mol Genet. 1999 Dec;8(13):2377-85. doi: 10.1093/hmg/8.13.2377.


Spinocerebellar ataxia type-3 or Machado-Joseph disease (SCA3/MJD) is a member of the CAG/polyglutamine repeat disease family. In this family of disorders, a normally polymorphic CAG repeat becomes expanded, resulting in expression of an expanded polyglutamine domain in the disease gene product. Experimental models of polyglutamine disease implicate the nucleus in pathogenesis; however, the link between intranuclear expression of expanded polyglutamine and neuronal dysfunction remains unclear. Here we demonstrate that ataxin-3, the disease protein in SCA3/MJD, adopts a unique conformation when expressed within the nucleus of transfected cells. The monoclonal antibody 1C2 is known preferentially to bind expanded polyglutamine, but we find that it also binds a fragment of ataxin-3 containing a normal glutamine repeat. In addition, expression of ataxin-3 within the nucleus exposes the glutamine domain of the full-length non-pathological protein, allowing it to bind the monoclonal antibody 1C2. Fractionation and immunochemical experiments indicate that this novel conformation of intranuclear ataxin-3 is not due to proteolysis, suggesting instead that association with nuclear protein(s) alters the structure of full-length ataxin-3 which exposes the polyglutamine domain. This conformationally altered ataxin-3 is bound to the nuclear matrix. The pathological form of ataxin-3 with an expanded polyglutamine domain also associates with the nuclear matrix. These data suggest that an early event in the pathogenesis of SCA3/MJD may be an altered conformation of ataxin-3 within the nucleus that exposes the polyglutamine domain.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal
  • Ataxin-3
  • Blotting, Western
  • Cell Line
  • Epitopes
  • Fluorescent Antibody Technique
  • Humans
  • Machado-Joseph Disease / genetics
  • Microscopy, Confocal
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Matrix / metabolism*
  • Nuclear Proteins
  • Peptides / chemistry*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Repressor Proteins
  • Transfection


  • Antibodies, Monoclonal
  • Epitopes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Repressor Proteins
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3