A novel mouse model for spinocerebellar ataxia type 3 containing 148 polyglutamine repeats

Spinocerebellar Ataxia Type 3 (SCA3) or Machado-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. SCA3 therefore belongs to the group of the so called polyglutamine diseases. In order to study the course of the disease we generated transgenic mouse models for this disorder. We used the prion protein (PrP) promotor to control the expression of the full length Ataxin-3 gene containing 70 or 148 CAG repeats, respectively. As controls transgenic mice expressing ataxin-3 with 15 CAG repeats were used. Western blot analyses confirmed the expression of the transgenic Ataxin-3 proteins in the brain. The mice carrying 148 polyglutamine repeats were severely affected by a remarkable neurological phenotype with aberrant behaviour, conspicuous footprint pattern as well as poor rotarod performance. 148 polyglutamine repeats in the Ataxin-3 protein lead to early death at about 15 weeks of age. Neuropathological examination by immunohistochemical staining revealed Ubiquitin- and Ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. The transgene containing 70 polyglutamine repeats give rise to a comparable but significant milder phenotype resulting in death at about 30 weeks of age. The phenotypical observations as well as the neuropathological results correspond to the mouse model with 148 CAG repeats. On the other hand mice carrying the Ataxin-3 transgene with a normal repeat length (15 CAG repeats) were phenotypically normal with no neuropathological findings. We believe that our mouse models will be a very helpful tool to study the progression of pathology in SCA3. In addition the different repeat numbers allow choosing from a more severe (148 repeats) or milder (77 repeats) phenotype.