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Aug. 24, 2009 — Proteins are essential for
all biological activities and the health of the cell. Misfolded and
damaged proteins spell trouble and are common to all human
neurodegenerative diseases and many other age-associated diseases. But
when during a lifespan do proteins start to misbehave?
A new Northwestern University study reports that protein damage can
be detected much earlier than we had thought, long before individuals
exhibit symptoms. But the study also suggests if we intervene early
enough, the damage could be delayed.
In studying seven different proteins of the worm C. elegans,
the researchers discovered that each protein misfolds at the same
point: during early adulthood and long before the animal shows any
behavioral, or physiological, change. (Each protein had a minor
mutation that affects folding.)
The misfolding coincided with the loss of a critical protective
cellular mechanism: the ability to activate the heat shock response, an
ancient genetic switch that senses damaged proteins and protects cells
by preventing protein misfolding.
The results will be published online during the week of Aug. 24 by the Proceedings of the National Academy of Sciences (PNAS).
"I didn't expect the results to be so dramatic, for these different
proteins that vary in concentration and are expressed in diverse
tissues to collapse at the same time," said lead researcher Richard I.
Morimoto. "This suggests the animal's protective cellular stress
response becomes deficient during aging."
Could the damaging events of protein misfolding be prevented or at least delayed?
To find out, the researchers gave the animals the equivalent of a
vitamin, boosting the heat shock response early in the animal's
development, prior to protein damage. Now, instead of misfolding around
day four, the equivalent of early adulthood in the worm, the proteins
didn't start misfolding until day 12. (Behavioral changes didn't appear
for at least three days after misfolding. The average lifespan of the
worm is 21 days.)
"Our data suggest that, in terms of therapeutics, you have to start
early to prevent damage and keep cells healthy," said Morimoto, Bill
and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell
Biology in Northwestern's Weinberg College of Arts and Sciences. "When
you see a loss of function, it's too late."
Genes that regulate lifespan were first discovered in C. elegans.
The transparent roundworm is a favorite organism of biologists because
its biochemical environment and fundamental mechanisms are similar to
that of human beings and its genome, or complete genetic sequence, is
The title of the PNAS paper is "Collapse of Proteostasis Represents
an Early Molecular Event in C. elegans Aging." In addition to Morimoto,
other authors of the paper are Anat Ben-Zvi and Elizabeth A. Miller,
both from Northwestern.
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