title: Polyglutamine-induced neurodegeneration in SCA3 is not mitigated by non-expanded ataxin-3: conclusions from double-transgenic mouse models.
abstract: A crucial question in polyQ-induced neurodegeneration is the influence of wild type protein on the formation of aggregates and toxicity. Recently it was shown that non-expanded ataxin-3 protein mitigated neurodegeneration in a Drosophila and mouse model of SCA3. We now explored the effects of overexpressing non-expanded ataxin-3 with 15Q in a SCA3 transgenic mouse model with 70 polyglutamine repeats. These double-transgenic mice (dt) developed neurological symptoms with premature death at the age of 6 months comparable to the single-transgenic (st) SCA3 disease model. Furthermore, immunohistochemistry revealed similar localization and distribution of nuclear aggregates in dt- and st-mutant SCA3 mice. In a second dt-mutant mouse model, coexpression of ataxin-3 with 148Q attached to a nuclear export signal, which usually diminishes the phenotype, did even reinforce toxic effects of mutant expanded ataxin-3. We therefore conclude that overexpressing wild type ataxin-3 or mutant ataxin-3 with NES are not striking suppressors of polyglutamine-induced neurodegeneration and have thus no potential for future gene therapeutic interventions in SCA3.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany. jeannette.huebener@med.uni-tuebingen.de
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hübener
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D049790:Nuclear Export Signals / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D049790:Nuclear Export Signals; D009687:Nuclear Proteins; D010455:Peptides; D014157:Transcription Factors; C097188:polyglutamine; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse