The International Journal of Biochemistry & Cell Biology
ReviewDecreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease
Introduction
A variety of diseases and physiological processes are characterized by the intra- or extracellular accumulation of proteins. These often cross-linked protein aggregates do not have a common terminology. Among others, the terms ‘protein aggregates’, ‘plaques’, ‘inclusion bodies’ or ‘aggresomes’ are used (Wojcik & DeMartino, 2003). Johnston, Ward, and Kopito (1998) defines an aggresome as “a pericentriolar, membrane-free, cytoplasmic inclusion containing misfolded, ubiquitinated proteins ensheeted in a cage of intermediate filaments formed specifically at the microtubuli organization center (MTOC)”. The term ‘inclusion body’ was used in a somewhat broader definition that does not include the microtubule dependence (Johnston et al., 1998). The term ‘protein aggregate’ appears to have a rather wide specificity, requiring mainly the existence of aggregations of misfolded protein. For extracellular protein aggregates the term ‘plaque’ is more common. The terms lipofuscin and ceroid are used in general to describe protein material that accumulates during the aging process. In a broader sense this describes accumulated intracellular protein materials that are also oxidized and modified by secondary reactions. Protein aggregation seems to be a common feature of many diverse neurodegenerative diseases, and of physiological aging.
Non-enzymatic protein modification and oxidation is a continuous process occurring in all cells. To prevent the accumulation of such non-functional proteins cells developed highly regulated intracellular proteolytic systems responsible for the removal of non-functional proteins. In the mammalian cell cytoplasm and nucleus the proteasomal system is responsible for the degradation of these non-functional proteins, while the lon protease has a similar role in mitochondria.
Section snippets
The Proteasome
Mammalian cells possess several major pathways for general protein degradation including lysosomal proteases, calcium-dependent proteases, the proteasomal system, and the mitochondrial lon protease. Proteins that enter cells from the outside, as well as several intracellular proteins (especially long-lived ones or proteins from various organelles), are degraded within lysosomes. Soluble intracellular cytoplasmic and nuclear proteins are degraded by the intracellular proteasomal system (Rock et
Oxidative stress, oxidized proteins and protein degradation
Oxidative stress is a condition referred to as an inbalance between oxidant generation and antioxidant systems. As a consequence of this phenomenon an enhanced amount of cellular oxidation products is formed (compared to physiological levels). The cellular oxidation products formed should be either repaired or removed, to prevent the accumulation of cellular debris. Only a limited number of oxidative protein changes can be enzymatically repaired; such as protein disulfides or methionine
Protein aggregates
Protein aggregates are oligomeric complexes of misfolded or unfolded proteins that would not normally be bound to each other. Protein aggregates are essentially insoluble and metabolically stable under normal physiological conditions (Johnston et al., 1998). The aggregate is unrelated to the original function of the protein, but introduces a new element into cellular metabolism, which might be toxic. It was estimated that about 30% of the newly synthesized proteins are misfolded (Fabunmi,
Protein aggregates and protein turnover
The occurrence of protein aggregates in cells may trigger a number of intracellular reactions, including the fact that the aggregates might act to promote cell death. Most protein aggregates are ubiquitinylated and the accumulation of intracellular ubiquitin conjugates leads to cell cycle arrest (Bence, Samapat, & Kopito, 2001). Furthermore, while the proteasomal system is inhibited by aggregates, regulatory proteins and transcription factors can not be degraded in good time, and thus may
Protein aggregates and protein turnover in aging and disease
Studies on age-related oxidative stress may have started with the discovery of age pigments by Hannover (1842). A relation between aging and the accumulation of this pigment was first proposed by Koneff (1886). The age related increase of age pigments was demonstrated in the 1970’s by Strehler et al. in human myocardium (Strehler, Mark, Mildvan, & Gee, 1959) and by Reichel et al. in rodent brain (Reichel, Holander, Clark, & Strehler, 1968). Later on this pigment was called lipofuscin, ceroid or
Acknowledgements
TG was supported by the DFG. KJAD was supported by grant number ES 03598 from the NIH/NIEHS.
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