Bringing Proteins into the Fold May Prevent Disease
Monday October 30, 2006 (1120 PST)
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ISLAMABAD: Folded the right way, proteins in the body perform their jobs as
efficiently as any well-designed factory machine. Folded the wrong way,
disease can strike.
Scientists in California have found a way to prevent proteins from misfolding
and thereby potentially prevent or at least arrest any one of hundreds of
"amyloid" diseases. The study was done in a laboratory setting, but tests on
humans are under way. "Ideally, if you knew who was at risk for the disease,
you would administer drugs prophylactically," says Jeff Kelly, senior author
of the study appearing in the Jan. 31 issue of Science.
"There's reason to believe that they could be useful after the disease
manifests itself clinically. I'm really optimistic that this will be useful
no matter how you do it -- as long as you do it, as long as people get
treated."
Amyloid diseases, which include Alzheimer's, Parkinson's, cystic fibrosis and
mad cow disease, result when misfolded proteins amass to form amyloids, which
are plaque-like structures that crowd different organs in the body.
Much research has focused on dealing with the amyloids once they are formed.
The authors of this study intervened a step earlier.
Under normal conditions, proteins fold themselves into three-dimensional
structures that then perform work much like screws and bolts, says Marc
Gillespie, a professor of pharmaceutical sciences at St. John's University in
Queens, N.Y. How, exactly, proteins acquire their specific shape has been a
bit of a mystery. "It's the equivalent of taking a string of pearls and
getting a steering wheel out of it," Gillespie says. The authors of this
study looked at a case of a protein gone awry: transthyretin amyloid
diseases, which involve misfolding of the protein transthyretin (TTR). TTR is
secreted by the liver into the bloodstream, where it acts as a transporter
for thyroid hormone and vitamin A.
Normal TTR is composed of four identical copies of the protein that bind to
each other. Certain genetic defects, however, cause this structure (called a
tetramer) to come apart easily, giving the parts the chance to change shape,
misfold, and come back together into the dreaded amyloid fibrils.
The researchers designed small molecules that bind to the TTR and provide a
stabilizing influence by requiring more energy to break it up.
The authors feel the strategy could work on the myriad of other amyloid
diseases, although others are not so sure.
"I think there are some real complications when we try to extend this to
Alzheimer's," says Bill Thies, vice president for medical and scientific
affairs for the Alzheimer's Association. "It's not clear whether it's the
accumulated amyloid that is the toxic species in Alzheimer's disease, so
there's no way of knowing whether interfering with folding would be a useful
technique."
It's also not clear that compounds that work in one part of the body would
also be able to penetrate the blood-brain barrier. "If we are going to impact
amyloid folding in the brain, then we are going to have to get into the
brain," Thies says.
Kelly, however, feels it's doable. And more results may appear sooner than
people think. Some of the compounds used in the Science paper are known drugs
and are also known to be safe. They are now being tested for efficacy.
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