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" diseases—particularly
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, and—in advanced
cases—failure 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 proteins—keeping 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
place—by 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
disease—both 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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