Study of the amyloidogenic conversion of V30M, S52P and V122I transthyretin variants by real-time Nuclear Magnetic Resonance: elucidation of the molecular mechanisms leading to different ATTR amyloidosis severity and different drug response.

Amyloidosis is a rare disease caused by abnormal deposition and accumulation of proteins in the tissues of the body. Amyloid deposits are primarily made up of protein fibres known as amyloid fibrils. These amyloid fibrils are formed when normally soluble body proteins aggregate and then remain in the tissues instead of safely going away. Amyloid deposits cause disease by gradually accumulating within organs and thereby disrupting the structure and damaging the function of the affected tissues. A blood protein called transthyretin (TTR) is the amyloid precursor protein that forms the amyloid deposits. The associated disease is called ATTR amyloidosis.  People who are born with inherited mutations in the TTR gene produce abnormal TTR. The variant TTR protein is amyloidogenic. Over the course of several decades, usually after the age of 30, people with inherited TTR gene mutations may develop symptoms of disease caused by the build-up of amyloid deposits. More than 130 different mutations in the TTR gene have been observed. Many of these can cause hereditary ATTR amyloidosis in which amyloid deposits containing variant TTR affect the nerves and/or the heart, and sometimes also the kidneys and eyes. Our study addresses the molecular mechanism of development of ATTR amyloidosis by revealing the atomic level structural changes that destabilize three prototypical selected variants in a specific manner. A new technique, called Rheo-NMR, will help in understanding the combined role of mechanical forces, also present in the heart, and enzymatic protein cleavage.