Generation and Initial Characterization of Ubiquilin Conditional Knockout Mouse

Robert Nicholas


Huntington’s disease is a hereditary neurodegenerative disorder due to a mutation on at least one of two copies of the huntingtin gene. The mutation is the result of an abnormally high number of trinucleotide (CAG) repeats which results in the toxic accumulation of poly-glutamine expanded Huntingtin protein in tissues of the nervous system. Recently, the protein ubiquilin-1 has been examined as a protein of interest in Huntington’s disease pathogenesis. Ubiquilin-1 functions as a transport between the polyubiquitinated proteins and the proteasome. Previous experiments have documented that overexpression of ubiquilin-1 results in reduced protein aggregate formation and decreased cell death. In this study, a ubiquilin-1 conditional knockout mouse was generated through LoxP/Cre-recombinase for the first time. This mouse was then in turn bred with the R6/2 mouse model of Huntington’s disease to create a Huntington disease mouse model deficient in the ubiquilin-1 gene. Protein analysis found that the genotype with ubiquilin-1 knocked out had a considerable increase in total polyubiquitinated proteins. Behavioral tests analyzed motor function in the mice and found that the genotype with no ubiquilin-1 expression had significantly inhibited motor ability. These results suggest that ubiquilin-1 has an important role in controlling protein aggregation in the brain and increasing its ability to assist in protein degradation could provide a unique pathway in controlling the pathogenesis of Huntington’s disease.