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 Previous Article

Molecular and Cellular Biology, February 2009, p. 1095-1106, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.01227-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process {triangledown} ,{dagger}

Ayako Tonoki,1 Erina Kuranaga,1,2 Takeyasu Tomioka,1 Jun Hamazaki,3 Shigeo Murata,3 Keiji Tanaka,4 and Masayuki Miura1,2*

Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,1 JST, CREST, Tokyo, Japan,2 Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,3 Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan4

Received 5 August 2008/ Returned for modification 8 September 2008/ Accepted 1 December 2008

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.

* Corresponding author. Mailing address: Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5841-4860. Fax: 81-3-5841-4867. E-mail: miura{at}mol.f.u-tokyo.ac.jp

{triangledown} Published ahead of print on 15 December 2008.

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

Molecular and Cellular Biology, February 2009, p. 1095-1106, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.01227-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zmijewski, J. W., Banerjee, S., Abraham, E. (2009). S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function. J. Biol. Chem. 284: 22213-22221 [Abstract] [Full Text]  


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