title: N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation.
abstract: Mutant ataxin-3 is aberrantly folded and proteolytically cleaved in spinocerebellar ataxia type 3. The C-terminal region of the protein includes a polyglutamine stretch that is expanded in spinocerebellar ataxia type 3. Here, we report on the analysis of an ataxin-3 mutant mouse that has been obtained by gene trap integration. The ataxin-3 fusion protein encompasses 259 N-terminal amino acids including the Josephin domain and an ubiquitin-interacting motif but lacks the C-terminus with the polyglutamine stretch, the valosin-containing protein binding region and part of the ubiquitin-interacting motif 2. Homozygous ataxin-3 mutant mice were viable and showed no apparent anatomical defects at birth. However, at the age of 9 months, homozygous and heterozygous mutant mice revealed significantly altered behaviour and progressing deficits of motor coordination followed by premature death at ∼12 months. At this time, prominent extranuclear protein aggregates and neuronal cell death was found in mutant mice. This was associated with disturbances of the endoplasmic reticulum-mediated unfolded protein response, consistent with the normal role of ataxin-3 in endoplasmic reticulum homeostasis. Thus, the ataxin-3 gene trap model provides evidence for a contribution of the non-polyglutamine containing ataxin-3 N-terminus, which mimics a calpain fragment that has been observed in spinocerebellar ataxia type 3. Consistent with the disease in humans, gene trap mice develop cytoplasmic inclusion bodies and implicate impaired unfolded protein response in the pathogenesis of spinocerebellar ataxia type 3.
authors.affiliation: Department of Medical Genetics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hübener
authors.forename: Franz
authors.initials: F
authors.lastname: Vauti
authors.forename: Claudia
authors.initials: C
authors.lastname: Funke
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Karen
authors.initials: K
authors.lastname: Wolburg-Buchholz
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.forename: Adriane
authors.initials: A
authors.lastname: Gardyan
authors.forename: Stefan
authors.initials: S
authors.lastname: Driessen
authors.forename: Hans-Henning
authors.initials: HH
authors.lastname: Arnold
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000067699:Ataxin-3; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000473:pathology / Q000648:ultrastructure*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D008124:Locomotion / Q000235:genetics; D017827:Machado-Joseph Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D008954:Models, Biological; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D012270:Ribosomes / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D010446:Peptide Fragments; D014157:Transcription Factors; D001616:beta-Galactosidase; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse