title: Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence.
abstract: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.
authors.affiliation: Department of Medical Genetics, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bichelmeier
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hübener
authors.forename: Jana
authors.initials: J
authors.lastname: Boy
authors.forename: Lukas
authors.initials: L
authors.lastname: Rüttiger
authors.forename: Karina
authors.initials: K
authors.lastname: Häbig
authors.forename: Sven
authors.initials: S
authors.lastname: Poths
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Schmidt
authors.forename: Johannes
authors.initials: J
authors.lastname: Wilbertz
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D001415:Back / Q000002:abnormalities; D002467:Cell Nucleus / Q000378:metabolism*; D005106:Exploratory Behavior; D007150:Immunohistochemistry / Q000379:methods; D002479:Inclusion Bodies / Q000378:metabolism; D017827:Machado-Joseph Disease / Q000150:complications* / Q000378:metabolism / Q000401:mortality / Q000523:psychology; D001523:Mental Disorders / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009410:Nerve Degeneration / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013194:Staining and Labeling; D014018:Tissue Distribution; D014202:Tremor / Q000209:etiology; D018911:Trinucleotide Repeats; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D025801:Ubiquitin; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3