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Oxidized proteins and their biological impact

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Aging is characterized by an increased accumulation of damaged macromolecules and oxidized protein build up is considered to be a hallmark of cellular aging. Advanced glycation end products (AGE) have been analyzed in aging human peripheral blood lymphocytes since such glycoxidative modifications have been reported to increase with age in a variety of cellular and tissular systems and are believed to contribute to the intracellular age-related accumulation of damaged proteins, a process that has been associated with the cellular functional deficits that occur with age. The pattern of glycated protein has been studied using two dimensional gel electrophoresis followed by Western blotting with an anti-AGE antibody. The protein silver stain and the immunoblot patterns were not superimposable indicating that glycoxidative modifications are targeting only a restricted set of proteins. Among these preferential protein targets, seven of them exhibited a significant age-related increased immunoreactivity with the anti-AGE antibody suggesting that the corresponding modified proteins might serve as biomarkers of aging lymphocytes [ 1]. Other age-related protein modifications such as carbonyl formation and conjugation with the lipid peroxidation product 4-hydroxy-2-nonenal are also currently studied. The age-related accumulation of altered protein raises the problem of the efficacy of intracellular protein maintenance, in particular the protein degradation and the protein repair systems. Indeed, if these systems that take care of the removal or repair of damaged proteins are affected with aging, they would therefore directly contribute to the increased intracellular load of functionally impaired protein. Since cytosolic oxidized protein degradation and basal protein turnover have been shown to be mostly carried out by the proteasomal system, the fate of proteasome in aging has been addressed and a decline of proteasomal proteolytic activity has been reported [ 2].

The impact of aging on human lymphocyte 26S proteasome has been recently investigated and age-related alterations of proteasome structure and function have been evidenced. Indeed, we observed a decline of 26S proteasome specific activity which is correlated to an increasing yield of post-translational modifications of proteasome subunits [ 3]. In fact, some proteasome subunits and particularly assembly and catalytic subunits are specifically modified with age. According to bidimensional westernblotting, some subunits were found either glycated, conjugated with the lipid peroxidation product 4-hydroxy-2-nonenal or even ubiquitinated. In vitro treatment of the proteasome by glyoxal, that promotes the formation of Nɛ-carboxymethyllysine adducts, or by the lipid peroxidation product 4-hydroxy-2-nonenal was found to inactivate its peptidase activities although to different extent. In other studies aimed at monitoring the effect of oxidative stress on proteasome structure and function, we have shown on an in vivo rat model that coronary occlusion/reperfusion resulted in inactivation of the proteasome [ 4]. This inactivation is associated with selective modification by the lipid peroxidation product 4-hydroxy-2-nonenal of three 20S proteasome α-subunits. In contrast, the observed inhibition of proteasome upon exposure of human keratinocytes to UV stress was mainly due to the stress-induced formation of endogeneous inhibitors, including certain oxidatively modified proteins [ 5]. In addition, the role of the peptide methionine sulfoxide reductase, one of the very few protein repair enzyme described, and its possible implication in the age-related decline of protein maintenance has been investigated. The peptide methionine sulfoxide reductase system (Msr A and Msr B) catalyzes the reduction of methionine sulfoxide to methionine within proteins and its activity and the expression of Msr A have been shown to decline in different organs of aged rats [ 6] and more recently in senescent human fibroblasts. Moreover, we have recently shown that the peptide methionine sulfoxide reductase Msr A is present both in the cytosol and in the mitochondrial matrix, although under different isoforms [ 7]. In conclusion, during aging or in certain oxidative stress situations, impairment of both peptide methionine sulfoxide reductases and proteasome activity appears as a critical factor in the decreased efficacy of intracellular protein maintenance, contributing to the increased intracellular load of modified and functionally impaired proteins that may ultimately lead to a global deterioration of cellular homeostasis.
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Document Type: Abstract

Affiliations: Laboratoire de Biologie et Biochimie Cellulaire du vieillissement, Université Paris VII, France

Publication date: April 1, 2004

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