Investigating the Mechanisms of Transthyretin Amyloid Aggregation
In transthyretin amyloidosis, also known as senile systemic amyloidosis when it occurs in the elderly, the protein transthyretin misfolds to precipitate into solid masses. This occurs to varying degrees over the course of aging for all of us, and it is becoming clear that these amyloid aggregates contribute meaningfully to the progression of heart disease, among other conditions. It also seems that transthyretin amyloidosis is what finally kills most supercentenarians, the oldest of people who evade every other fatal age-related condition.
There is a potential therapy to break down this form of amyloid that last year demonstrated very promising results in a human clinical trial, but it is currently locked into the slow regulatory path to availability; development has been ongoing for most of the last decade at a glacial pace. It is frustrating, given that this or a similar treatment should be used by pretty much everyone over the age of 40 every few years, and such a treatment should reduce the incidence of many fatal age-related conditions. Meanwhile, other research groups are continuing their investigations of the mechanisms of this form of amyloidosis and considering potential approaches to clearing transthyretin amyloid:
The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of TTR causes life-threatening transthyretin amyloidosis (ATTR) associated with three conditions traditionally known as senile systemic amyloidosis, familial amyloidotic polyneuropathy, and familial amyloidotic cardiomyopathy. Senile systemic amyloidosis is a late onset disease in which Tafamidis, a TTR tetramer stabilizer, has been recently approved in Europe; it delays progression of the disease. Several other therapeutics are currently in clinical trials, including other tetramer stabilizers such as diflunisal and RNAi therapies that cause a decrease in the production of TTR protein. Additional approaches are needed to prevent ATTR, and here we explore the use of peptide inhibitors that block aggregation of TTR.
Several models of the TTR amyloid spine have been proposed, but the aggregation-prone segments of the protein remain uncertain. Based on the studies of crystal structures of amyloid-driving segments, our group has proposed that fibrils can form through intermolecular self-association of one to several fibril-driving segments. Identical segments from several protein molecules stack into steric zipper structures, which form the spine of the amyloid fibril through tightly interdigitated β-sheets. Here we identify two segments of TTR that drive protein aggregation by self-association and formation of steric zipper spines of amyloid fibrils. Based on the amyloid structure of these two segments, we designed two peptide inhibitors that halt the progression of TTR aggregation.