Direct cellular delivery of human proteasomes to delay tau aggregation.

Research paper by Dong Hoon DH Han, Hee-Kyung HK Na, Won Hoon WH Choi, Jung Hoon JH Lee, Yun Kyung YK Kim, Cheolhee C Won, Seung-Han SH Lee, Kwang Pyo KP Kim, Jeff J Kuret, Dal-Hee DH Min, Min Jae MJ Lee

Indexed on: 06 Dec '14Published on: 06 Dec '14Published in: Nature communications


The 26S proteasome is the primary machinery that degrades ubiquitin (Ub)-conjugated proteins, including many proteotoxic proteins implicated in neurodegeneraton. It has been suggested that the elevation of proteasomal activity is tolerable to cells and may be beneficial to prevent the accumulation of protein aggregates. Here we show that purified proteasomes can be directly transported into cells through mesoporous silica nanoparticle-mediated endocytosis. Proteasomes that are loaded onto nanoparticles through non-covalent interactions between polyhistidine tags and nickel ions fully retain their proteolytic activity. Cells treated with exogenous proteasomes are more efficient in degrading overexpressed human tau than endogenous proteasomal substrates, resulting in decreased levels of tau aggregates. Moreover, exogenous proteasome delivery significantly promotes cell survival against proteotoxic stress caused by tau and reactive oxygen species. These data demonstrate that increasing cellular proteasome activity through the direct delivery of purified proteasomes may be an effective strategy for reducing cellular levels of proteotoxic proteins.