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It was reported in the CRS archives in the
http://tinyurl.com/create.php
message that protein folding may play a role in aging. A
recent paper (1) examined diseases occurring later in life
for the role of difficulties of protein processing. A new
review (2) highlights the details, with and emphasis on the
involvement of inflammation.

1. Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A.
Opposing activities protect against age-onset proteotoxicity.
Science. 2006 Sep 15;313(5793):1604-10. Epub 2006 Aug 10.
PMID: 16902091

Aberrant protein aggregation is a common feature of late-onset
neurodegenerative diseases, including Alzheimer's disease,
which is
associated with the misassembly of the Abeta(1-42) peptide.
Aggregation-mediated Abeta(1-42) toxicity was reduced in
Caenorhabditis
elegans when aging was slowed by decreased insulin/insulin
growth
factor-1-like signaling (IIS). The downstream transcription
factors, heat
shock factor 1, and DAF-16 regulate opposing disaggregation
and aggregation
activities to promote cellular survival in response to
constitutive toxic
protein aggregation. Because the IIS pathway is central to
the regulation of
longevity and youthfulness in worms, flies, and mammals,
these results
suggest a mechanistic link between the aging process and
aggregation-mediated proteotoxicity.

Stress, Aging, and Neurodegenerative Disease
R. I. Morimoto
New Engl J Med 355:2254-2255 November 23, 2006 Number 21

Aging and stress, stress and aging - these two human
conditions, when
paired, can profoundly affect the quality of life. When
events go awry,
molecular processes take place that, over time, can lead to
neurodegenerative disease. At the root of the problem is a
fundamental
process: protein folding. Since proteins are the predominant
products of
gene expression and provide much of the shape and
functionality of the cell,
their proper synthesis, folding, assembly, translocation,
and clearance are
essential for the health of the cell and the organism. When
proteins
misfold, they can acquire alternative proteotoxic states
that seed a cascade
of deleterious molecular events resulting in cellular
dysfunction. When
these events occur in neurons, the consequences can be
devastating.

Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis,
Huntington's disease, and other neuropathies involve the
cytopathological
appearance of intracellular and extracellular protein
aggregates in the
brains of affected persons. It is increasingly clear that
the relevant event
in these neurodegenerative diseases is a toxic
gain-of-function mutation
associated with the appearance of oligomers and other toxic
aggregates
consisting of the -amyloid peptide, -synuclein, superoxide
dismutase, and
huntingtin, respectively. The way in which these toxic
species form, the
processes that determine their persistence or clearance, and
the molecular
basis of their toxicity are critical to the mechanisms of
these diseases.

Because the necessity of correct protein folding is common
to all forms of
life, many insights have been provided by studies of
organisms such as the
yeast Saccharomyces cerevisiae and the invertebrates
Caenorhabditis elegans
and Drosophila melanogaster. One such study was recently
reported by Cohen
and colleagues.1 It builds on a previous study showing that
two factors
determine the cellular toxicity of mutant huntingtin in a
worm model of
disease: the length of the mutant polyglutamine repeat (the
substantive
expansion of which causes disease in humans) and the
expression of proteins
in the insulin-signaling pathway that regulate the life
span.2 The idea that
the molecular determinants of longevity might influence
polyglutamine-mediated toxicity is supported by observations
that the length
of time until disease develops - days in C. elegans, weeks
in D.
melanogaster, months in mice, and years in humans -
correlates approximately
with the life span of the organism. The association between
the life span
and the cellular stress response is suggested by the
insulin-signaling
pathway's requirement for heat-shock factor 1 (HSF-1), the
activator of the
heat-shock response that induces the expression of molecular
chaperones (a
large class of proteins that assist in protein folding and
thus guard
against misfolding) during stress.3,4 Consequently, the
inhibition of HSF-1
function also increases polyglutamine aggregation, resulting
in toxic
effects that decrease the life span of C. elegans. Conversely,
overexpression of HSF-1 suppresses polyglutamine-mediated
toxicity and
extends the life span. Collectively, these observations
provide support for
the hypothesis that graceful aging depends on the cell's
ability to counter
the effects of stress by maintaining protein folding, which
in turn permits
appropriate protein function.

Cohen et al. showed that activation of the insulin-signaling
pathway
suppresses the toxicity of aggregates of amyloid 42, the
peptide found in
lesions in the brains of patients with Alzheimer's disease.
With the use of
a C. elegans model that expresses amyloid 42, these
investigators showed
that in suppressing the toxicity of aggregates, the
insulin-signaling
pathway activates two downstream pathways, both of which
affect the fate of
an aggregation-prone protein. Each pathway is triggered by a
transcription
factor: HSF-1 or abnormal dauer formation 16 (DAF-16). The
authors showed
that HSF-1 promotes disaggregation by elevating the levels
of protective
molecular chaperones, whereas DAF-16 enhances the formation
of large, inert
aggregates from toxic oligomers (Figure 1).

Figure 1. A Model of Age-Related Protection against
Proteotoxicity. The
insulin-signaling pathway is triggered in C. elegans by a
receptor called
DAF-2. It has a profound effect on aging - a mutation of
daf2 can result in
a doubling of the life span of this organism, and similar
results have been
observed in mice. DAF-2 represses two downstream pathways:
one is
commandeered by the transcription factor HSF-1 and the other
by the
transcription factor DAF-16. (Transcription factors are
proteins that "turn
on" specific genes.) A recent study by Cohen et al.1 shows
that both HSF-1
and DAF-16 provide protection against proteotoxicity of the
amyloid 42
peptide, an aggregation-prone peptide that can spontaneously
form small
toxic aggregates. The default pathway, regulated by HSF-1,
identifies and
breaks apart toxic aggregates. When the HSF-1 machinery is
overloaded,
however, a molecular apparatus regulated by DAF-16 grinds
into gear,
resulting in the formation of less toxic
high-molecular-weight aggregates.

Although these activities might appear to oppose one
another, Cohen and
colleagues proposed an intriguing hierarchy of cellular
protection
mechanisms. They suggested that HSF-1 is the first line of
defense against
damaged proteins, initiating the expression of molecules
that recognize and
disaggregate the nascent oligomeric and aggregate species.
DAF-16 may
provide a secondary line of defense against the toxic
oligomers that escape
from HSF-1-mediated clearance by converting them into large,
inert
aggregates. HSF-1 and DAF-16 have many downstream gene
targets, so it will
be important to identify those genes that are key to
disaggregation or
aggregation.

Cohen et al. also observed that the amyloid 42 peptide
expressed in their C.
elegans model appears to exert its toxic effects in the
cytoplasm of the
cell. This finding challenges the notion that extracellular
plaques in
Alzheimer's disease are the sole basis of toxic effects.

The study reported by Cohen et al. shows that cellular
degeneration in
diseases of protein conformation is unlikely to be caused by
a single
defect; instead, it is likely to be the net consequence of
cumulative
insults to the quality control of protein folding, resulting
in deleterious
effects on multiple cellular processes. Although the authors
do not
explicitly say as much, this study suggests the promise of
new therapeutic
strategies that harness existing cellular mechanisms to
prevent the
widespread disruption of protein homeostasis.