Abstract
Ubiquilin proteins have been implicated in the cause and the pathology of neurodegenerative diseases. In the R6/2 mouse model of Huntington's disease (HD), ubiquilin levels decline during disease progression. Restoration of their levels by transgenic expression of ubiquilin-1 extends survival. Here we provide a comprehensive assessment of the expression and localization of all four ubiquilin proteins in both normal and R6/2-affected mice brains, using antibodies specific for each protein. Ubiquilin-1, 2 and 4 proteins were detected throughout the brain, with increased expression seen in the hippocampus and cerebellum. Ubiquilin-3 expression was not detected. All three ubiquilins expressed in the brain were found in Htt inclusions. Their expression changed during development and disease. Ubiquilin-1 and ubiquilin-2 protein levels decreased from 6 to 18 weeks of mouse development, independent of disease. Ubiquilin-1 and ubiquilin-4 protein levels also changed during HD disease progression. Ubiquilin-4 proteins that are normally expressed in the brain were lost and instead replaced by a novel 115 kDa higher molecular weight immunoreactive band. Taken together, our results demonstrate that all ubiquilin proteins are involved in HD pathology and that distinct changes in the signature of ubiquilin-4 expression could be useful for monitoring end-stage of HD disease.