Biomedical Engineering Reference
In-Depth Information
Chapter 7
Cellular Stress and Protein Misfolding During Aging
Rajiv Vaid Basaiawmoit and Suresh I.S. Rattan
Abstract
Cells are under constant onslaught from several intrinsic and extrinsic stressors, which lead to the occurrence
and accumulation of molecular damage, functional impairment, aging, and eventual death. Protein mis-
folding is both a cause and a consequence of increased cellular stress. An age-related failure of the com-
plex systems for handling protein misfolding results in the accumulation of misfolded and aggregated
proteins, and consequent conformational diseases. However, some misfolded proteins have been found
to be both toxic and, in some cases, protective, highlighting the various complex, dynamic, and interde-
pendent mechanisms at play. Molecular mechanisms are being elucidated for the occurrence of protein
misfolding and for its prevention by chaperones and various pathways of degradation. Insights from the
knowledge about proteodynamics are likely to impact future interventional strategies to counter stress
and to promote healthy aging by preventing and/or treatment of protein conformational diseases.
Key words:
Abnormal proteins, Protein turnover, Proteasome, Lysosome, Proteostasis, Proteodynamics
1. Introduction
Aging at the molecular level is characterised by the progressive
accumulation of molecular damage in DNA, RNA, lipids, and
proteins (
1
). An age-related increase in the levels of structurally
and functionally abnormal proteins is a universally observed phe-
nomenon (
2, 3
). A variety of stressors have been implicated in the
occurrence and increase of abnormal proteins during aging, of
which oxidative stress is a major contributor. Chronic oxidative
stress can lead to protein misfolding or unfolding, resulting in
proteins unable to carry out their normal functions and thus ini-
tiating a breakdown of various cellular events. Mammalian cells
have various maintenance, repair, and removal systems to counter-
act such events, and include the GroEL chaperone pathway to refold
proteins (
4
), the ubiquitin-mediated proteosomal degradational
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