An international research team reveals new molecular mechanisms associated with pathogenic mutations in the protein transthyretin that cause transthyretin amyloidosis (ATTR), a group of fatal progressive diseases. The results, obtained thanks to a new methodological approach, open the door to the development of drugs with higher therapeutic potential, designed specifically for the variants of the protein associated with the disease.
The study has been published in the journal Proceedings of the National Academy of Sciences. The study was led by researchers from the Institute of Biotechnology and Biomedicine of the Universitat Autònoma de Barcelona (IBB-UAB) and Washington University in St. Louis.
Understanding transthyretin and ATTR
Transthyretin (TTR) is a protein produced primarily in the liver and, to a lesser extent, in the brain. A series of genetic mutations cause the misfolding and aggregation of TTR, which accumulates as amyloid fibers in various tissues. This accumulation causes a set of progressive and fatal clinical disorders known as transthyretin amyloidosis (ATTR), which can affect the nervous system, heart, and other vital organs.
High-resolution X-ray diffraction studies have determined more than 300 TTR structures, but these provide a static image of the protein and do not capture the effects pathogenic mutations cause on TTR stability and conformation. Some small molecules (binding ligands) have been developed to counteract the effects of these mutations, but currently approved drugs have a generic activity and do not offer specific therapeutic response for the different phenotypic variants of the disease. This highlights the need to design new stabilizers adapted to each specific mutation.