The proteasome and its function in the ageing process

Abstract

The ageing process is characterized by a progressive loss of function and a decline in the functional capacities of the organism, leading to death. The nature of the processes involved in loss of functions is not well understood. A number of theories have been proposed, including a hypothesis that emphasizes the role of reactive oxygen species as a fundamental causal factor in the ageing process; among other things, oxidative damage to proteins through reactive oxygen species plays a key role in the ageing process. Oxidative modification of proteins generally causes them to become dysfunctional, and normally to undergo preferential degradation. Within the cell the main proteolytic machinery involved in the degradation of oxidized proteins is the proteasomal system, consisting of a multicatalytic protease complex--the proteasome--and numerous regulatory factors. The proteasome is a highly conserved structure that is distributed in the cytosol, nucleus and endoplasmatic reticulum of mammalian cells. As the proteasome itself is also exposed to oxidative stress during the ageing process several studies were carried out to investigate the role and the activity of the proteasomal system during ageing. This review will describe current knowledge of the activity of the protesomal system and its possible involvement in the ageing process.

Inhibition of apoptosis in acute promyelocytic leukemia cells leads to increases in levels of oxidized protein and LMP2 immunoproteasome

“…1 B and C). This finding supports the proposition (19) that loss of apoptotic capacity may contribute to the accumulation of oxidized proteins as occurs during aging and in the development of some age-related diseases (1)(2)(3)(4)(5)(6). This proposition is based on the consideration that when animals reach maturity, many of their organs become fixed in size.…”

“…The intracellular levels of oxidized proteins have been shown to increase during aging and in the development of many age-related diseases, including Alzheimer's disease, rheumatoid arthritis, atherosclerosis, and Parkinson's disease (1)(2)(3)(4)(5)(6). Moreover, an increase in intracellular ROS leads to initiation of various types of cell death (7).…”

Proteasome inhibition modulates kinase activation in neural cells: Relevence to ubiquitination, ribosomes, and survival

“…In particular, studies are needed to distinguish which downstream effects of proteasome inhibition are involved in promoting neurotoxicity, as well as identify those cellular disturbances which play a role in preventing neurotoxicity in response to proteasome inhibition. Such data are of significant importance in the neuroscience field given the considerable evidence for proteasome inhibition contributing to brain aging and neuropathology in a variety of neurodegenerative disorders (Keller et al, 2006; Olanow and McNaught, 2006; Stolzing and Grune, 2001; Sullivan et al, 2004; Halliwell, 2002; McNaught, 2004; Seo et al, 2004). Studies using N2a cells may therefore be combined with studies in primary rat neurons to develop useful insight into these areas of aging and neurodegeneration research.…”

Molecular alterations in proteasomes of rat liver during aging result in altered proteolytic activities

“…The second major pathway responsible for intracellular protein degradation is catalysed by the ubiquitinproteasome system (UPS), whose involvement in the aging process has been intensively investigated (for review, see Carrard et al 2002;Chondrogianni and Gonos 2005;Gaczynska et al 2001;Merker et al 2001;Stolzing and Grune 2001;Vernace et al 2007). The proteolytically active core of the UPS is the 20S proteasome, a cylinder-shaped complex composed of four seven-membered rings of α-and β-subunits.…”