Spinocerebellar ataxia type 3 (SCA3), also known as Machado Joseph disease (MJD), is the second most common polyglutamine disorder. SCA3 is caused by an expanded CAG repeat in the penultimate exon of the ATXN3 gene. This mutant CAG repeat results in the translation of an expanded ataxin-3 protein. Neuropathological studies have detected widespread neuronal loss in the cerebellum, thalamus, midbrain, pons, medulla oblongata and spinal cord of SCA3 patients. The ataxin-3 protein contains an amino-terminal Josephin domain that displays ubiquitin protease activity and a carboxyl-terminal tail with 2 or 3 ubiquitin interacting motifs (UIMs), depending on the isoform. It is still not completely understood how the ataxin-3 polyglutamine expansion results in the observed pathology.
In the Neuro-D group we study the role of the different functional domains of the ataxin-3 protein and how the functions of the ataxin-3 protein change in SCA3, using patient fibroblasts and iPSCs, and SCA3-transgenic mice.
Figure: SCA3 molecular pathology