Gene reprogramming by K48R mutant ubiquitin in a mouse model of SCA1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease resulting from the loss of Purkinje neurons within the cerebellum. The causative agent of the disease is the expansion of a trinucleotide repeat in its gene product ataxin-1. The ubiquitin proteasome pathway (UPP) has been implicated in SCA1 but the role of proteolysis in the disease is still poorly understood. To further investigate this issue in vivo , genetic crosses were performed between a well established mouse model of SCA1 and novel strains expressing elevated levels of wild type or mutant isoforms of ubiquitin. The K48R mutant isoform of ubiquitin (a dominant negative inhibitor of proteolysis) was found to significantly delay the deterioration of Purkinje neurons as evidenced by behavioral, morphological, and molecular indicators. This delay was accompanied by the restoration of genes involved in calcium and glutamate signalling and by the stabilization of postsynaptic density proteins whose abundance/activity would otherwise decline in the course of the SCA1 disease. These results are consistent with transcriptional dysregulation as a key mechanism in neurodegeneration and suggest that the UPP is a useful target for the development of novel therapies.