title: A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats.
abstract: Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is caused by the expansion of a polyglutamine repeat in the ataxin-3 protein. We generated a mouse model of SCA3 expressing ataxin-3 with 148 CAG repeats under the control of the huntingtin promoter, resulting in ubiquitous expression throughout the whole brain. The model resembles many features of the disease in humans, including a late onset of symptoms and CAG repeat instability in transmission to offspring. We observed a biphasic progression of the disease, with hyperactivity during the first months and decline of motor coordination after about 1 year of age; however, intranuclear aggregates were not visible at this age. Few and small intranuclear aggregates appeared first at the age of 18 months, further supporting the claim that neuronal dysfunction precedes the formation of intranuclear aggregates.
authors.affiliation: Medical Genetics, University of Tuebingen, Tuebingen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Boy
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schumann
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.forename: Samy
authors.initials: S
authors.lastname: Unser
authors.forename: Carsten
authors.initials: C
authors.lastname: Holzmann
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.forename: Tim
authors.initials: T
authors.lastname: Karl
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Saleh
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D017668:Age of Onset; D000818:Animals; D000067699:Ataxin-3; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D043171:Chromosomal Instability / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051381:Rats; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse