Abstract
Prion diseases are fatal neurodegenerative disorders characterized by the accumulation of prion protein (PrPC). To date, there is no effective treatment for the disease. The accumulated PrP, termed PrPSc, forms amyloid fibrils and could be infectious. It has been suggested that PrPSc 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 PrPC. 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 PrPC, as well as PrPSc, levels in prion-infected neuronal cells. Overexpression of the dominant negative mutant form of USP14 reduced PrPSc, whereas wildtype USP14 increased PrPSc 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 PrPSc clearance caused by USP14 might contribute greatly to the development of therapeutic strategies for prion diseases.
Highlights
Has been shown that endogenous USP14 negatively regulates ERAD19
Lee et al demonstrated that IU1, a selective small-molecule inhibitor of USP14, accelerated proteasomal degradation of tau and TDP-43, which have been implicated in neurodegenerative diseases[21]
Degradation, mouse neuroblastoma N2a cells expressing endogenous PrP (N2a58 cells) were treated with 100 μ M IU1, an agent that inhibits the function of USP1421, for 24 or 48 h
Summary
Has been shown that endogenous USP14 negatively regulates ERAD19. USP14 overexpression inhibits degradation of the null Hong Kong mutant α 1-antitrypsin, an ER luminal unfolded protein of ERAD substrate[20], whereas USP14 depletion by small interfering RNA effectively accelerates its degradation. Lee et al demonstrated that IU1, a selective small-molecule inhibitor of USP14, accelerated proteasomal degradation of tau and TDP-43, which have been implicated in neurodegenerative diseases[21]. We focused on the USP14 system to reveal PrPC degradation in the proteasome, and investigated whether USP14 is related to regulation of prion protein degradation. Results demonstrated that an inhibitor of USP14 reduced PrPC in mouse neuroblastoma cells, as well as PrPSc, indicating that USP14 negatively regulates degradation of prion protein
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