Cellular Stress and Protein Misfolding During Aging - Protein Misfolding and Cellular Stress in Disease and Aging - page 105

machinery to remove misfolded proteins ( 5 ), and lysosomal
autophagy to sequester and degrade larger aggregates ( 6 ).
Inefficient protein turnover by both proteasomal and lysosomal
pathways are generally considered to be the main reason for the
accumulation of abnormal proteins during aging ( 1 ). Recently,
however, protein misfolding and its deleterious consequences have
emerged as the crucial mediators of impaired cellular functions and
increased cellular stress during aging. This is also underscored by
observations that resistance to protein folding damage and proper
protein folding over time correlate with species-specific longevity
( 7, 8 ). Thus, tight control of protein folding and misfolding seems
to be the key in regulating cellular stress during aging.
It is well recognised that properly folded proteins are necessary
for their efficient and accurate functions. Since the first demon-
stration by C. Anfinsen in 1973 that it is the primary amino acid
sequence that determines the final protein structure ( 9 ), it is now
well accepted that protein folding in vitro is many times simpler
than what is known to happen in vivo. A remarkable fact in protein
folding is the observation that proteins can fold in the millisecond
timescale in a complex environment in which other proteins and
macromolecules like DNA, RNA, and lipids populate the cellular
space in concentration ranges of 300-400 mg/ml ( 10 ). This
amazing biological feat clearly points out that protein folding is
not an isolated event but is a “team event” with a number of
molecules within this crowded interior assisting in the formation
of the final correctly folded product. Thus, to attain proper
function in the complex environment of a cell, appropriate mecha-
nisms have evolved for folding proteins in the “right way,” which
overall comprise what is also known as the protein “quality control
system.”
The term “misfolded” proteins refers both to proteins that
are unable to form a well-structured compact fold and to proteins
that have attained a compact fold but a wrong one with the wrong
amino acids resulting in aberrant or promiscuous functionality.
What the term does not refer to is a new class of proteins that
have been recently identified as functional proteins lacking a com-
pact fold - the so-called “unfolded proteome” ( 11, 12 ). In this
article, we review the basic mechanisms governing the process of
protein folding, the occurrence of misfolding, and how it contrib-
utes towards increasing cellular stress during aging.
2. Protein Folding:
A Team Event
Like all biological processes, protein folding requires energy, and
is a mechanism that follows the basic thermodynamic principles.
It has also been demonstrated that the folding process searches