Mechano-enzymatic cleavage of transthyretin in systemic amyloidosis: elucidation of mechanism and characterization of putative proteases

点击翻译按钮获取中文摘要

Amyloidosis is a group of rare, serious and usually fatal diseases, responsible for the deaths of about one per thousand people who die in developed countries. It is caused by deposition of abnormal, insoluble, protein fibres, known as amyloid, in the tissues and organs of the body including the heart, kidneys, bowel, nerves and skin. Amyloid is derived by transformation of the body's own normal proteins into a mass of solid amyloid fibres; this leads to disruption and eventually organ failure. Transthyretin (TTR) is one of these "amyloidogenic" proteins and can result in a familial (hereditary) form of the disease. TTR amyloid also occurs in the elderly, making TTR amyloidosis a disease of ageing with profound clinical and socio-economic consequences. We have recently discovered that plasmin, an important enzyme in the normal blood clotting process is important in the development of TTR amyloid fibrils. Under conditions which are found in the heart, this enzyme breaks down TTR and leads directly to the formation of amyloid fibres. We will look at all the steps in the formation of TTR amyloid, particularly looking at the effects of both currently available and newly developed drugs. We will examine the relationship between the physiological (normal) pathway of blood clotting and the pathogenic (abnormal) pathway of TTR fibrillogenesis. Plasmin not only breaks down blood clots but may also activate the formation of amyloid by our newly discovered route. Our new understanding of how these two natural systems interact will allow us to evaluate the effect of anti-plasmin drugs on TTR amyloid formation. We believe that this work will improve our understanding of the causes of TTR amyloidosis, but will also be of major interest to the mechanism of other protein misfolding diseases.