Protein Homeostasis in Models of Aging and Age-Related Conformational Disease

Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, 2205 Tech Drive, Hogan 2-100, Northwestern University, Evanston, Illinois 60208, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 01/2010; 694:138-59. DOI: 10.1007/978-1-4419-7002-2_11
Source: PubMed

ABSTRACT The stability of the proteome is crucial to the health of the cell, and contributes significantly to the lifespan of the organism. Aging and many age-related diseases have in common the expression of misfolded and damaged proteins. The chronic expression of damaged proteins during disease can have devastating consequences on protein homeostasis (proteostasis), resulting in disruption ofnumerous biological processes. This chapter discusses our current understanding of the various contributors to protein misfolding, and the mechanisms by which misfolding, and accompanied aggregation/toxicity, is accelerated by stress and aging. Invertebrate models have been instrumental in studying the processes related to aggregation and toxicity of disease-associated proteins and how dysregulation ofproteostasis leads to neurodegenerative diseases of aging.

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    • "Failures in the PQC system can lead to the loss of protein biological function or to the formation of aggregated species, which have been implicated in the aging process and to the development of conformational diseases [2] [4] [5] [6] [7] [8]. "
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    ABSTRACT: Proteins participate in almost every cell physiological function, and to do so, they need to reach a state that allows its function by folding and/or exposing surfaces of interactions. Spontaneous folding in the cell is in general hindered by its crowded and viscous environment, which favors misfolding and nonspecific and deleterious self-interactions. To overcome this, cells have a system, in which Hsp70 and Hsp90 play a central role to aid protein folding and avoid misfolding. The topics of this review include the biophysical tools used for monitoring protein-ligand and protein-protein interactions and also some important results related to the study of molecular chaperones and heat shock proteins (Hsp), with a focus on the Hsp70/Hsp90 network. The biophysical tools and their use to probe the conformation and interaction of Hsp70 and Hsp90 are briefly reviewed.
    Current Protein and Peptide Science 05/2015; 16(8). DOI:10.2174/1389203716666150505225744 · 3.15 Impact Factor
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    • "Complex pathways to ensure proteostasis in different subcellular compartments, defined as unfolded protein responses (UPRs), have evolved in the cytosol, endoplasmic reticulum and mitochondria, which are finely coordinated and require a close communication with the nucleus. Dysfunction of proteostasis is associated with protein aggregation and is a feature of several age-related diseases (Kikis et al., 2010). While the unfolded protein response in the endoplasmic reticulum (UPR ER ) and the cytosolic heat shock response (HSR) have been extensively studied (Vabulas et al., 2010; Walter and Ron, 2011), the mitochondrial unfolded protein response (UPR mt ) was more recently discovered and sheds light on the complex relationships between this organelle and the nucleus (Haynes and Ron, 2010). "
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    ABSTRACT: The ability to respond to various intracellular and/or extracellular stresses allows the organism to adapt to changing environmental conditions and drives evolution. It is now well accepted that a progressive decline of the efficiency of stress response pathways occurs with aging. In this context, a correct proteostasis is essential for the functionality of the cell, and its dysfunction has been associated with protein aggregation and age-related degenerative diseases. Complex response mechanisms have evolved to deal with unfolded protein stress in different subcellular compartments and their moderate activation translates into positive effects on health. In this review, we focus on the mitochondrial unfolded protein response (UPR(mt)), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death. We compare UPR(mt) with the extensively characterized cytosolic heat shock response (HSR) and the unfolded protein response in endoplasmic reticulum (UPR(ER)), and discuss the current knowledge about UPR(mt) signaling pathways as well as their potential involvement in physiology.
    Journal of Experimental Biology 01/2014; 217(Pt 1):137-43. DOI:10.1242/jeb.090738 · 2.90 Impact Factor
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    • "A major risk factor for most PMDs, in particular neurodegenerative diseases, is aging [9]. This finding suggests that aged cells and tissues are more prone to form and accumulate misfolded aggregates. "
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    ABSTRACT: The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself.
    International Journal of Cell Biology 11/2013; 2013:638083. DOI:10.1155/2013/638083
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