Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process

Abstract

The intracellular accumulation of unfolded or misfolded proteins is believed to contribute to aging and age-related neurodegenerative diseases. However, the links between age-dependent proteotoxicity and cellular protein degradation systems remain poorly understood. Here, we show that 26S proteasome activity and abundance attenuate with age, which is associated with the impaired assembly of the 26S proteasome with the 19S regulatory particle (RP) and the 20S proteasome. In a genetic gain-of-function screen, we characterized Rpn11, which encodes a subunit of the 19S RP, as a suppressor of expanded polyglutamine-induced progressive neurodegeneration. Rpn11 overexpression suppressed the age-related reduction of the 26S proteasome activity, resulting in the extension of flies' life spans with suppression of the age-dependent accumulation of ubiquitinated proteins. On the other hand, the loss of function of Rpn11 caused an early onset of reduced 26S proteasome activity and a premature age-dependent accumulation of ubiquitinated proteins. It also caused a shorter life span and an enhanced neurodegenerative phenotype. Our results suggest that maintaining the 26S proteasome with age could extend the life span and suppress the age-related progression of neurodegenerative diseases.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank T. Aigaki, N. Bonini, W. Carthew, and R. Ueda for materials and flies and the Bloomington Stock Center and the Drosophila Genetic Resource Center (Kyoto Institute of Technology) for fly stocks. We also thank H. Kanuka for valuable discussions and all members of the Miura laboratory for technical support and helpful advice.

This work was supported by grants from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (to M.M. and E.K.). This work was also supported in part by a grant from the Cell Science Research Foundation (to M.M.), a Riken Bioarchitect research grant (to M.M.), the Uehara Memorial Foundation (to E.K.), and the Takeda Science Foundation (to E.K.). A.T. is a research fellow of the Japan Society for the Promotion of Science.