Impairment of proteasome structure and function in aging.
Damage to macromolecules, and in particular protein, implicated in the cellular degeneration that occurs during the aging process, is corroborated by the accumulation of oxidative end-products over time. Oxidized protein build up is commonly seen as a hallmark of cellular aging. Protein turnover is essential to preserve cell function and the main proteolytic system in charge of cytosolic protein degradation is the proteasome. The proteasome is a multi-catalytic proteolytic complex, which recognizes and selectively degrades oxidatively damaged and ubiquitinated proteins. One of the hypothesis put forward to explain the accumulation of altered proteins is the decrease of proteasome activity with age. Indeed, accumulation of altered protein can be explained by increased protein alteration, decreased protein degradation or the combination of both. A short description of proteasome structure and of its role in cellular functions is first given. Then, accumulation of damaged protein is presented with emphasis on the pathways implicated in the formation of altered proteins. Finally, evidence for an age-related impairment of proteasome structure and function that has been reported by different groups is provided in the light of proteasomal dysfunction induced upon oxidative stress. It is now clear that proteasome activity is declining with age and that the loss in proteasome activity during aging is dependent of at least three different mechanisms: decreased proteasome expression; alterations and/or replacement of proteasome subunits and formation of inhibitory cross-linked proteins. However, it is also clear that events leading to the age- and disease-related loss of proteasome function have not yet been fully characterized.
Laboratoire de Biologie et Biochimie Cellulaire du Vieillissement, Université Paris 7, Denis Diderot, 2 place Jussieu, 75251 Cedex 05, Paris, France.
Géraldine
G
Carrard
Anne-Laure
AL
Bulteau
Isabelle
I
Petropoulos
Bertrand
B
Friguet
D000375:Aging / Q000502:physiology*; D000818:Animals; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits
D009097:Multienzyme Complexes; D016877:Oxidants; D021122:Protein Subunits; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex