Scientists Discover a New Approach for Treating "Misfolding Diseases"
By Jason Socrates Bardi
Professor Jeffery W. Kelly and his colleagues in the Department of Chemistry
and The Skaggs Institute for Chemical Biology at The Scripps Research
Institute (TSRI) have demonstrated a new approach for treating "amyloid"
diseasesparticularly transthyretin amyloid diseases, which are similar
to Parkinson's and Alzheimer's.
These amyloid diseases are caused by proteins misfolding into a structure
that leads them to cluster together, forming microscopic fibril plaques
made up of hundreds of these misfolded proteins. The plaques deposit in
internal organs and interfere with normal function, sometimes lethally.
In the current issue of the journal Science, Kelly and his TSRI
colleagues demonstrate the efficacy of using small molecules to stabilize
the normal "fold" of transthyretin, preventing this protein from misfolding.
Using this method, researchers were able to inhibit the formation of fibrils
by a mechanism that is known to ameliorate disease.
"I'm very excited about pursuing these potential therapeutic opportunities,"
says Kelly, the report's lead author. Kelly is the Lita Annenberg Hazen
Professor of Chemistry in The Skaggs Institute for Chemical Biology and
vice president of academic affairs at TSRI.
Misfolding Causes Disease
Familial amyloid polyneuropathy (FAP) is a collection of over 80 rare
amyloid diseases caused by the misfolding of the protein transthyretin
(TTR), which the liver secretes into the bloodstream to carry thyroid
hormone and vitamin A. Normally, TTR circulates in the blood as an active
"tetramer" made up of four separate copies, or protein subunits, that
bind to each other.
These tetramers, normally composed of identical protein subunits, come
from two different genes. When one of the genes has a heritable defect,
hybrid tetramers form that are composed of mutant and normal subunits.
The inclusion of mutated subunits makes the tetramer less stable and causes
the four subunits to more easily dissociate. Once the subunits are free,
they misfold and reassemble into the hair-like amyloid fibrils. These
fibrils cause the disease FAP by building up around peripheral nerve and
muscle tissue, disrupting their function and leading to numbness, muscle
weakness, andin advanced casesfailure of the autonomic nervous
system including the gastrointestinal tract. The current treatment for
FAP is a liver transplant, which replaces the mutant gene with a normal
copy.
An analogous disease called familial amyloid cardiomyopathy (FAC) causes
fibril formation in the heart, which leads to cardiac dysfunction. About
one million African-Americans carry the gene that predisposes them to
FAC. Another amyloid disease affecting the heart, Senile Systemic Amyloidosis
(SSA), afflicts an estimated 10 to 15 percent of all Americans over the
age of 80.
Some therapeutic approaches that have previously been tried involve
administering drugs that inhibit the growth of fibrils from the misfolded
state. However, this often proves ineffective because fibril formation
is strongly favored once an initial, misfolded "seed" fibril forms.
Kelly's approach is to prevent amyloid formation by stabilizing the
native state of proteinskeeping them folded in their proper form.
Instead of preventing the misfolded protein subunits from conglomerating
to form plaques, he is attempting to prevent them from becoming abnormal
monomeric subunits in the first placeby stabilizing the tetrameric
"native state" of the protein.
Stabilization Through Binding
Last year, Kelly and his colleagues discovered that TTR tetramers composed
of both disease-associated and suppressor subunits ameliorate disease
by stabilizing the tetramer, thus preventing the disease-associated subunits
from contributing to fibril formation. They found that even one such suppressor
subunit incorporated into a tetramer otherwise composed of disease-associated
subunits doubles its stability.
"The suppressor TTR subunits prevent misfolding by blocking tetramer
dissociation accomplished by raising the barrier associated with this
process," says Kelly.
In the current study, Kelly and his colleagues found that the mechanism
by which small molecules inhibit amyloidogenesis is analogous to the mechanism
by which trans-suppression prevents diseaseboth increase the barrier
associated with misfolding. The small molecules bind to the TTR protein
and stabilize the tetramer, making it harder for the subunits to dissociate.
Since trans-suppression is known to prevent disease onset in humans, there
is good reason to be optimistic that the small molecule approach will
be effective in humans.
"The same approach may also work with other amyloid diseases," says
Kelly. "Any protein that misfolds and causes pathology that interacts
with another protein or has a small molecule binding site could, in principle,
be targeted [with a trans-suppression approach or a small molecule strategy
to treat disease]."
The article, "Prevention of Transthyretin Amyloid Disease by Changing
Protein Misfolding Energies" is authored by Per Hammarstrom, R. Luke Wiseman,
Evan T. Powers, and Jeffery W. Kelly and appears in the January 31, 2003
issue of the journal Science.
The research was funded in part by the National Institutes of Health,
TSRI's Skaggs Institute for Chemical Biology, the Lita Annenberg Hazen
Foundation, and through a postdoctoral fellowship sponsored by the Wenner-Gren
Foundation.
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