When it comes to deadly protein clusters
in the brain, size matters.
The human equivalent of mad cow disease,
variant Creutzfeldt-Jakob disease (vCJD) is thought to be caused by
misshapen proteins, known as prions, that infect the brain. Research
now shows that the most infectious strings of prions are of a
middling length; clumps that are longer or shorter are less
problematic.
The findings, reported in this week's
Nature1,
could convince medical experts to rethink how they plan to treat
illnesses such as vCJD, as well as Alzheimer's and Parkinson's.
Model hamsters
Researchers have often debated whether
longer or shorter chains of prions are more problematic. The
molecules seem to multiply by converting the normal proteins that
they touch to an irregular form. Long ones form visible tangles in
the brain, but short ones might be more capable of spreading the
infection.
Jay Silveira and his colleagues at the Rocky Mountain
Laboratories in Hamilton, Montana, obtained misshapen prion proteins
from hamsters, broke them up using a detergent, and sorted them
according to size. They then injected strings of known length into
other hamsters.
One group of four hamsters received
protein chains that were 21 prions long, and these animals all
succumbed to the disease after about 90 days. Hamsters receiving a
solution with protein chains more than 300 prions long died after 90
days only if the solution of prions was 70 times more concentrated,
making these longer chains some 70 times less dangerous.
Hamsters
given six-unit chains stayed healthy for an additional month, and
the concentration needed to cause illness indicated that such short
clusters are some 600 times less infectious than the 21-prion
chains. Very few of the animals receiving chains of five or fewer
prions seemed to get sick at all, living a normal hamster lifespan
of two years, says Silveira.
Block and break
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Several
of the experimental treatments being used on prion diseases such as
vCJD aim to block the formation or spread of misshapen proteins. In
animal models, many of the treatments seem to work better before the
onset of symptoms.
Silveira notes that breaking up prion
clusters could be another method, if approached cautiously. "If you
could break them up small enough, you could potentially remove their
pathogenicity," he says. "The problem would be getting to those
small ones without going through the intermediate sizes."
The finding
also has implications for treatments of Alzheimer's and Parkinson's
disease. In both of these illnesses, long protein threads form in
the brain. Silveira and colleagues caution against therapies for
these diseases that might fragment these molecular chains into more
problematic, moderate lengths.
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