Aktuelle Neurologie 2007; 34 - V37
DOI: 10.1055/s-2007-987449

Are neurodegerative processes in SCA3 reversible? A study using transgenic mouse models

J Boy 1, T Schmidt 1, U Schumann 1, J Horst 1, TB Leergaard 1, F Odeh 1, S Nuber 1, S Beck 1, C Holzmann 1, S Ibrahim 1, U Grasshoff 1, I Schmitt 1, F Zimmermann 1, M Seeliger 1, S Prusiner 1, JG Bjaalie 1, O Rieß 1
  • 1Tübingen; Oslo, N; Rostock, Bonn, Heidelberg; San Francisco, USA

Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph-Disease (MJD) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG stretch in the MJD1 gene encoding a polyglutamine repeat in the respective ataxin-3-protein. In order to study the course of the disease, we generated an inducible transgenic mouse model using the “Tet-Off-System“. This system is based on two constructs: The promoter construct controls the expression of the so called tTA (Tetracycline transactivator) gene product. The binding of this protein to a Tetracycline responsive element (TRE) in the responder construct induces the transcription of the gene of interest. The expression can be blocked by the addition of Tetracycline or Doxycycline which allosterically inhibits the tTA protein. For the ataxin-3-responder mouse lines, a full length constructs containing an expanded repeat with the pathological length of 77 glutamine repeats was used. The use of two different promoter mouse lines with known expression in the brain (Prion protein (Prp) promoter, Ca2+/Calmoduline-dependent protein kinase II (CamKII) promoter) allows us to target the transgene expression to different brain regions. In preceding promoter analyses we identified and characterized these brain regions in detail. Using the CamKII promoter, the trangene is targeted mainly to the frontal brain and mice display first symptoms at the age of six months. However, when we use the Prp promoter, the transgene is widely expressed in the brain with pronounced expression in the cerebellum and the brain stem. In these mice, first motor symptoms can be detected at the age of two months. We then stopped the expression of the transgene by treatment with doxycyclin and compared treated and untreated mice at different levels: We first analysed the phenotype in behavioural studies. Afterwards we performed immunohistochemical analyses of brain sections to study the expression of the transgene and neurodegenerative processes in the brain. These analyses revealed that turning off the pathogenic transgene at least slows down the progression of symptoms but did not reverse the phenotype. Comparable approaches in human patients -if available- would therefore require early initiation.