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Preferential degradation of oxidized proteins by the 20S proteasome may be inhibited in aging and in inflammatory neuromuscular diseases

From the Ethel Percy Andrus Gerontology Center and the Division of Molecular & Computational Biology, University of Southern California, Los Angeles, CA.

Address correspondence and reprint requests to Dr. Kelvin J. A. Davies, University of Southern California, 3715 McClintock Avenue, GER 306, Los Angeles, CA 90089-0191; e-mail: Kelvin{at}usc.edu

Free radicals produced by chronic inflammation cause cumulative damage to cellular macromolecules and appear to contribute to senescence/aging, age-related disorders, and neuromuscular degenerative diseases such as inclusion-body myositis. Proteins are major targets for oxidative damage (in addition to DNA and lipids) and the accumulation of oxidized proteins has been reported in many aging and disease models. In young and healthy individuals, moderately oxidized soluble cell proteins are selectively and rapidly degraded by the 20S proteasome. The mechanism of selective proteolysis appears to depend upon oxidation-induced protein unfolding, with increasing surface hydrophobicity as (previously shielded) hydrophobic residues are exposed from the interior. The 20S proteasome can preferentially bind to and degrade such mildly oxidized, hydrophobic proteins without a need for ubiquitin targeting or ATP activation. Severely oxidized, aggregated, and crosslinked proteins, however, are poor substrates for degradation and actually inhibit the proteasome. During aging, and in many age-related diseases/disorders, the proteasome is progressively inhibited by binding to increasing levels of oxidized and cross-linked protein aggregates. Cellular aging and inflammatory neuromuscular degenerative diseases probably include both an increase in the generation of reactive oxygen species as well as a decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence.

This article was previously published in electronic format as an Expedited E-Pub at www.neurology.org.

The research underlying this review paper was supported by NIH/NIEHS grant # ES03598 to KJAD.

Disclosure: The authors report no conflicts of interest.

Received June 22, 2005. Accepted in final form October 14, 2005.

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