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.

Mutations in ATP13A2 cause Kufor-Rakeb syndrome (KRS), a juvenile form of Parkinson’s disease (PD) with dementia. However, the mechanisms by which mutations in ATP13A2 cause KRS is not understood. The mutations lead to misfolding of the translated Atp13a2 protein and its premature degradation in the endoplasmic reticulum, never reaching the lysosome where the protein is thought to function. Atp13a2 is a P-type ATPase, a class of proteins that function in ion transport. Indeed, studies of human, mouse, and yeast Atp13a2 proteins suggest a possible involvement in regulation of heavy metal toxicity. Here we report on the cytoprotective function of Atp13a2 on HeLa cells and dopamine neurons of Caenorhabditis elegans (C . elegans) . HeLa cells stably overexpressing V5- tagged Atp13a2 Isoform-1 protein were more resistant to elevated manganese exposure and to starvation-induced cell death compared to cells not overexpressing the protein. Because PD is characterized by loss of dopamine neurons, we generated transgenic C . elegans expressing GFP-tagged human Atp13a2 protein in dopamine neurons. The transgenic animals exhibited higher resistance to dopamine neuron degeneration after acute exposure to manganese compared to nematodes that expressed GFP alone. The results suggest Atp13a2 Isoform-1 protein confers cytoprotection against toxic insults, including those that cause PD syndromes.