Review
Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease

https://doi.org/10.1016/j.biocel.2004.04.020Get rights and content

Abstract

Protein aggregation seems to be a common feature of several neurodegenerative diseases and to some extent of physiological aging. It is not always clear why protein aggregation takes place, but a disturbance in the homeostasis between protein synthesis and protein degradation seems to be important. The result is the accumulation of modified proteins, which tend to form high molecular weight aggregates. Such aggregates are also called inclusion bodies, plaques, lipofuscin, ceroid, or ‘aggresomes’ depending on their location and composition. Such aggregates are not inert metabolic end products, but actively influence the metabolism of cells, in particular proteasomal activity and protein turnover. In this review we focus on the influence of oxidative stress on protein turnover, protein aggregate formation and the various interactions of protein aggregates with the proteasome. Furthermore, the formation and effects of protein aggregates during aging and neurodegeneration will be highlighted.

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.

References (117)

  • B. Friguet et al.

    Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. Formation of cross-linked protein that inhibits the multicatalytic protease

    J. Biol. Chem.

    (1994)
  • J. Gieche et al.

    Protein oxidation and proteolysis in RAW264.7 macrophages: Effects of PMA activation

    Biochim. Biophys. Acta

    (2001)
  • T. Grune et al.

    Peroxynitrite increases the degradation of aconitase and other cellular proteins by proteasome

    J. Biol. Chem.

    (1998)
  • T. Grune et al.

    Protein oxidation and proteolysis by the nonradical oxidants singlet oxygen or peroxynitrite

    Free Radic. Biol. Med.

    (2001)
  • T. Grune et al.

    Degradation of oxidized proteins in K562 human hematopoietic cells by proteasome

    J. Biol. Chem.

    (1996)
  • T. Grune et al.

    Proteolysis in cultered liver epithelial cells during oxidative stress: Role of the multicatalytic proteinase complex, proteasome

    J. Biol. Chem.

    (1995)
  • W. Hilt et al.

    Proteasomes: Destruction as a programme

    TIBS

    (1996)
  • J. Jahngen-Hodge et al.

    Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress

    J. Biol. Chem.

    (1997)
  • Y. Kato et al.

    Immunohistochemical detection of dityrosine in lipofuscin pigments in the aged human brain

    FEBS Lett.

    (1998)
  • M.L. Katz et al.

    Lysine methylation of mitochondrial ATP synthase subunit c stored in tissues of dogs with hereditary ceroid lipofuscinosis

    J. Biol. Chem.

    (1994)
  • J.N. Keller et al.

    The proteasome in brain aging

    Ageing Res. Rev.

    (2002)
  • A.F. Kisselev et al.

    Binding of hydrophobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of the 20S proteasomes. Evidence for peptide-induced channel opening in the alpha rings

    J. Biol. Chem.

    (2002)
  • R.R. Kopito

    Aggresomes, inclusion bodies and protein aggregation

    Trends Cell Biol.

    (2000)
  • P.T. Lansbury

    Structural neurology: Are seeds at the root of neuronal degeneration?

    Neuron

    (1997)
  • P. Lasch et al.

    Hydrogen peroxide-induced structural alterations of RNaseA

    J. Biol. Chem.

    (2001)
  • K. Merker et al.

    Proteolysis, caloric restriction and aging

    Mech. Aging Dev.

    (2001)
  • R.E. Pacifici et al.

    Protein degradation as an index of oxidative stress

    Methods Enzym.

    (1990)
  • R.E. Pacifici et al.

    Macroxyproteinase (M.O.P.): A 670 kDa proteinase complex that degrades oxidatively denaturated proteins in red blood cells

    Free Radic. Biol. Med.

    (1989)
  • B.J. Passer et al.

    Interaction of Alzheimer’s presenilins with Bcl-XL: A potential role in modulating the threshold of cell death

    J. Biol. Chem.

    (1999)
  • H.L. Paulson et al.

    Intranuclear inculsions of expanded polyglutamine protein in spinocerebellar ataxia type 3

    Neuron

    (1997)
  • G. Pawelec et al.

    Finite life spans of T cell clones derived from CD34+ human hematopoietic stem cells in vitro

    Exp. Gerontol.

    (1999)
  • J.M. Peters

    Proteasomes. Protein degradation machines of the cell

    TIBS

    (1994)
  • M. Rechsteiner et al.

    The multicatalytic and the 26S proteases

    J. Biol. Chem.

    (1993)
  • T. Reinheckel et al.

    Differential impairment of 20S and 26S proteasome activities in human hematopoietic K562 cells during oxidative stress

    Arch. Biochem. Biophys.

    (2000)
  • A.J. Rivett

    Preferential degradation of the oxidatively modified form of glutamine synthetase by intracellular mammalian proteases

    J. Biol. Chem.

    (1985)
  • A.J. Rivett

    Purification of a liver alkaline protease which degrades oxidatively modified glutamine synthetase. Characterization as a high molecular weight cysteine proteinase

    J. Biol. Chem.

    (1985)
  • A.J. Rivett

    Intracellular distribution of proteasomes

    Curr. Opin. Immunol.

    (1998)
  • K.L. Rock et al.

    Inhibitors of proteasome block the degradation of most cell proteins and the generation of peptides on MHC class I molecules

    Cell

    (1994)
  • D.C. Salo et al.

    Superoxide dismutase undergoes proteolysis and fragmentation following oxidative modification and inactivation

    J. Biol. Chem.

    (1990)
  • F. Shang et al.

    Activity of ubiquitin-dependent pathway in response to oxidative stress

    J. Biol. Chem.

    (1997)
  • M.Y. Sherman et al.

    Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases

    Neuron

    (2001)
  • R. Shringarpure et al.

    Ubiquitin-conjugation is not required for the degradation of oxidized proteins by the proteasome

    J. Biol. Chem.

    (2003)
  • N. Sitte et al.

    Proteasome-dependent degradation of oxidized proteins in MRC-5 fibroblasts

    FEBS Lett.

    (1998)
  • O. Sommerburg et al.

    Dose- and wavelength-dependent oxidation of crystallins by UV light—selective recognition and degradation by the 20S proteasome

    Free Radic. Biol. Med.

    (1998)
  • B. Anselmi et al.

    Dietary self-selection can compensate an age-related decrease of rat liver 20S proteasome activity observed with standard diet

    J. Gerontol.

    (1998)
  • A.S. Baldwin

    The NF-κB and I-κB proteins: New discoveries and insights

    Annu. Rev. Immunol.

    (1996)
  • T. Beal et al.

    The hydrophobic effect contributes to polyubiquitin chain recognition

    Biochemistry

    (1998)
  • D. Bence et al.

    Impairment of the Ubitquitin-Proteasome system by protein aggregation

    Science

    (2001)
  • W. Carmichael et al.

    Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease

    Proc. Natl. Acad. Sci. U.S.A.

    (2000)
  • J.M. Carney et al.

    Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-a-phenylnitone

    Proc. Natl. Acad. Sci. U.S.A.

    (1991)
  • Cited by (575)

    View all citing articles on Scopus
    View full text