TSRI Scientists Discover a Therapeutic Strategy for "Misfolding
Diseases" Analogous to Alzheimer's Disease
By Jason Socrates
Investigator 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 uncovered a
potentially useful strategy to treat the rare disease familial
amyloid polyneuropathy (FAP)an approach that may be
generally useful for intervention in other amyloid diseases.
In the current issue of the journal Science, the
team demonstrates that it is possible to prevent the protein
shape changes that cause FAP, a disease that is analogous
to Alzheimer's. The strategy is to introduce another protein
that interacts with the protein capable of aberrant shape
changes, preventing them.
"I'm very excited about pursuing these potential therapeutic
opportunities," says Kelly.
Amyloid-forming diseases like FAP are generally characterized
by the formation of microscopic fibrils made up of hundreds
of misfolded proteins that cluster together and deposit in
organs, interfering with their normal function.
FAP, a rare amyloid disease, is caused by the misfolding
of the protein transthyretin (TTR), which is secreted by the
liver 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 subunits come from two different genes on two different
chromosomes. The resulting tetramers are composed of identical
protein subunits when the genes are identical.
However, when one of the copies 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 dissociate under
conditions where they are not supposed to. Once the subunits
are free, they can misfold and reassemble into the hair-like
These fibrils cause the disease FAP by building up around
peripheral nerve and muscle tissue, disrupting their function
and leading to numbness and muscle weakness, andin advanced
casesfailure of the gastrointestinal tract. The current
treatment for FAP is a liver transplant, which replaces the
mutant gene with a normal copy.
Kelly and his colleagues discovered that a "suppressor"
TTR subunit incorporated into a TTR tetramer with disease-associated
destabilizing subunits prevents the tetramer from dissociating
into potential fibril-forming monomers. Significantly, they
found that incorporating even one of the suppressor subunit
into a tetramer where the remainder of the subunits have disease-associated
mutations doubles its stability. "The suppressor protein subunits
prevent misfolding by preventing dissociation," says Kelly.
This "trans" suppression approach may form the basis for
a new therapy for FAP, in which a patient could receive an
injection of the suppressor protein. The idea may also work
with other diseases where the protein normally engages in
protein-protein interactions. When gene therapy becomes practical,
one may be able to introduce the suppressor gene directly
into the organ that makes the aberrant protein. The protective
subunit will therefore be incorporated during biosynthesis,
thus preventing later misfolding.
The research article, "Trans-Suppression of Misfolding
in an Amyloid Disease" is authored by Per Hammarstrom, Frank
Schneider, and Jeffery W. Kelly and appears in the September
28, 2001 issue of the journal Science.
The research was funded in part by the National Institutes
of Health, The Skaggs Institute for Chemical Biology and the
Lita Annenberg Hazen Foundation.
Jeffery Kelly is Lita Annenberg Hazen
Professor of Chemistry, vice president of academic affairs,
and dean of graduate studies. Photo by Michael Balderas.
Trans-Suppression of Misfolding: A transthyretin
tetramer composed exclusively of disease-associated V30M mutant
monomers (green subunits in left panel) readily dissociates
and misfolds causing amyloid fibril formation (background
micrograph in left panel). Kelly and coworkers find that incorporating
one T119M suppressor monomer (red subunit in the tetramer,
center panel) reduces fibril formation two-fold. Incorporating
additional T119M suppressor subunits (right panel) stops tetramer
dissociation completely and prevents transthyretin misfolding,
thus inhibiting fibril formation. Click
on image to enlarge.