SCA4 locus-associated gene Ronin (Thap11) increases Ataxin-1 protein levels and induces cerebellar degeneration in a mouse model of ataxia

ABSTRACT Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous inherited neurodegenerative disorders characterized by progressive ataxia and cerebellar degeneration. Here, we tested if Ronin (Thap11), a polyglutamine-containing protein encoded in a region on human chromosome 16q22.1 that has been genetically linked to SCA4, can be connected with SCA disease in a mouse model. We report that transgenic expression of Ronin in mouse cerebellar Purkinje cells leads not only histopathologically to detrimental loss of Purkinje cells but also phenotypically to the development of severe ataxia as early as 10-12 weeks after birth. Mechanistically, we find that Ronin is part of a protein complex in the cerebellum that is distinct from the one previously found in embryonic stem cells. Importantly, ectopically expressed Ronin raises the protein level of Ataxin-1 (Atxn1), the causative gene of the most common type of SCA, SCA1. Hence, our data provide evidence for a link between Ronin and SCAs, and also suggest that Ronin may be involved in the development of other neurodegenerative diseases.