A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats

Jana Boy, Thorsten Schmidt, Ulrike Schumann, Ute Grasshoff, Samy Unser, Carsten Holzmann, Ina Schmitt, Tim Karl, Franco Laccone, Hartwig Wolburg, Saleh Ibrahim, Olaf Riess

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageBritish English
Pages (from-to)284-293
Number of pages10
JournalNeurobiology of Disease
Volume37
Issue number2
DOIs
StatePublished - Feb 2010

Keywords

  • CAG repeat instability
  • Intranuclear inclusion bodies
  • Late onset
  • Machado-Joseph disease
  • MJD
  • Polyglutamine
  • SCA3
  • Spinocerebellar ataxia type 3
  • Transgenic mouse model

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