Mitochondria-associated apoptosis in the pathogenesis of SCA3

Machado-Joseph disease (MJD) or Spinocerebellar Ataxia Type 3 (SCA3) is the most common type of SCA worldwide. SCA3 is an autosomal dominant neurodegenerative disorder caused by polyglutamine-expanded ataxin-3, whose function is still unknown. To better understand the function of Ataxin-3 in vivo, we analysed Ataxin-3 mutant mice generated by the gene trap (GT) approach. The genetrap model harboured a truncated ataxin-3 including the Josephin domain and the first ubiquitin inactive motif (UIM1), but lacking the VCP binding site and the polyQ stretch. By expressing only the Josephin domain and UIM1 we got a SCA3 like phenotype with an onset of symptoms at the age of one year with a reduced lifespan. In the brain of this model we found cytoplasmic inclusion bodies induced most likely by the Josephin domain. This supports the hypotheses that the Josephin domain can cause similar symptoms as the polyQ stretch and forms aggregates, too. We further analyzed the influence of ataxin-3 in the ERAD system in the genetrap model and found that mitochondria-associated apoptosis might be involved in the pathogenesis in SCA3. In in vivo and in vitro experiments we found differential regulated genes with are involved in the mitochondrial-associated apoptosis. The data would be analysed by western blot, quantitative real time analysis, electron microscopy and biochemical analysis.