title: Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex.
abstract: Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by ataxia and selective neuronal cell loss caused by the expansion of a translated CAG repeat encoding a polyglutamine tract in ataxin-7, the SCA7 gene product. To gain insight into ataxin-7 function and to decipher the molecular mechanisms of neurodegeneration in SCA7, a two-hybrid assay was performed to identify ataxin-7 interacting proteins. Herein, we show that ataxin-7 interacts with the ATPase subunit S4 of the proteasomal 19S regulatory complex. The ataxin-7/S4 association is modulated by the length of the polyglutamine tract whereby S4 shows a stronger association with the wild-type allele of ataxin-7. We demonstrate that endogenous ataxin-7 localizes to discrete nuclear foci that also contain additional components of the proteasomal complex. Immunohistochemical analyses suggest alterations either of the distribution or the levels of S4 immunoreactivity in neurons that degenerate in SCA7 brains. Immunoblot analyses demonstrate reduced levels of S4 in SCA7 cerebella without evident alterations in the levels of other proteasome subunits. These results suggest a role for S4 and ubiquitin-mediated proteasomal proteolysis in the molecular pathogenesis of SCA7.
authors.affiliation: Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112-5331, USA.
authors.forename: A
authors.initials: A
authors.lastname: Matilla
authors.forename: C
authors.initials: C
authors.lastname: Gorbea
authors.forename: D D
authors.initials: DD
authors.lastname: Einum
authors.forename: J
authors.initials: J
authors.lastname: Townsend
authors.forename: A
authors.initials: A
authors.lastname: Michalik
authors.forename: C
authors.initials: C
authors.lastname: van Broeckhoven
authors.forename: C C
authors.initials: CC
authors.lastname: Jensen
authors.forename: K J
authors.initials: KJ
authors.lastname: Murphy
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
authors.forename: Y H
authors.initials: YH
authors.lastname: Fu
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D000067719:Ataxin-7; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D018076:DNA, Complementary; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D009097:Multienzyme Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D021381:Protein Transport; D020754:Spinocerebellar Ataxias / Q000378:metabolism* / Q000473:pathology; D020798:Two-Hybrid System Techniques
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D018076:DNA, Complementary; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000251:Adenosine Triphosphatases; C109306:S4 ATPase, proteasome