TSRI Scientists Discover a Therapeutic Strategy for "Misfolding Diseases" Analogous to Alzheimer's Disease

By Jason Socrates Bardi

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 amyloid fibrils.

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, and—in advanced cases—failure 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.