Human Molecular Genetics Advance Access originally published online on August 10, 2009
Human Molecular Genetics 2009 18(22):4282-4295; doi:10.1093/hmg/ddp381
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Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3
1 Department of Medical Genetics, 2 Institute for Pathology and 3 Institute for Anatomy, University of Tuebingen, D-72076 Tuebingen, Germany, 4 Clinic for Neurology, University of Bonn, D-53127 Bonn, Germany, 5 Department of Medical Genetics, University of Rostock, D-18055 Rostock, Germany, 6 Center for Molecular Biology, University of Heidelberg, D-69120 Heidelberg, Germany and 7 San Raffaele Scientific Institute, I-20132 Milan, Italy
* To whom correspondence should be addressed at: Department of Medical Genetics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany. Tel: +49 70712976458; Fax: +49 7071295228; Email: olaf.riess{at}med.uni-tuebingen.de
Received March 13, 2009; Accepted August 5, 2009
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a CAG repeat tract that affects the MJD1 gene which encodes the ataxin-3 protein. In order to analyze whether symptoms caused by ataxin-3 with an expanded repeat are reversible in vivo, we generated a conditional mouse model of SCA3 using the Tet-Off system. We used a full-length human ataxin-3 cDNA with 77 repeats in order to generate the responder mouse line. After crossbreeding with a PrP promoter mouse line, double transgenic mice developed a progressive neurological phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired Rotarod performance and lower body weight gain. When ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. These results show that reducing the production of pathogenic ataxin-3 indeed may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time.