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 e
Contact: Jason Bardi
Scripps Research Institute