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Prion diseases are fatal neurodegenerative disorders characterized by the accumulation of prion protein (PrP C ). To date, there is no effective treatment for the disease. The accumulated PrP, termed PrP Sc , forms amyloid fibrils and could be infectious. It has been suggested that PrP Sc  is abnormally folded and resistant to proteolytic degradation, and also inhibits proteasomal functions in infected cells, thereby inducing neuronal death. Recent work indicates that the ubiquitin-proteasome system is involved in quality control of PrP C . To reveal the significance of prion protein ubiqitination, we focused on ubiquitin-specific protease 14 (USP14), a deubiqutinating enzyme that catalyzes trimming of polyubiquitin chains and plays a role in regulation of proteasomal processes. Results from the present study showed that treatment with a selective inhibitor of USP14 reduced PrP C , as well as PrP Sc , levels in prion-infected neuronal cells. Overexpression of the dominant negative mutant form of USP14 reduced PrP Sc , whereas wildtype USP14 increased PrP Sc  in prion-infected cells. These results suggest that USP14 prevents degradation of both normal and abnormal PrP. Collectively, a better understanding about the regulation of PrP Sc  clearance caused by USP14 might contribute greatly to the development of therapeutic strategies for prion diseases.

Ubiquitin-specific protease 14 modulates degradation of cellular prion protein