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

淀粉样变性是一组罕见、严重且通常致命的疾病，在发达国家，每千人中约有一人死于淀粉样变性。它是由不正常的，不溶性的，蛋白质纤维，称为淀粉样蛋白，在身体的组织和器官，包括心脏，肾脏，肠，神经和皮肤沉积引起的。淀粉样蛋白是由身体自身的正常蛋白质转化为大量的固体淀粉样蛋白纤维而产生的;这会导致破坏并最终导致器官衰竭。甲状腺素运载蛋白（TTR）是这些“淀粉样”蛋白质之一，并可导致家族性（遗传性）形式的疾病。TTR淀粉样蛋白也发生在老年人中，使得TTR淀粉样变性成为具有深刻临床和社会经济后果的衰老疾病。我们最近发现纤溶酶（正常血液凝固过程中的一种重要酶）在TTR淀粉样纤维的发育中非常重要。在心脏中发现的条件下，这种酶分解TTR并直接导致淀粉样纤维的形成。我们将研究TTR淀粉样蛋白形成的所有步骤，特别是研究现有药物和新开发药物的作用。我们将研究凝血的生理（正常）途径和TTR纤维形成的致病（异常）途径之间的关系。纤溶酶不仅可以分解血凝块，还可以通过我们新发现的途径激活淀粉样蛋白的形成。我们对这两个自然系统如何相互作用的新理解将使我们能够评估抗纤溶酶药物对TTR淀粉样蛋白形成的影响。我们相信，这项工作将提高我们对TTR淀粉样变性的原因的理解，但也将是其他蛋白质错误折叠疾病的机制的主要兴趣。

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.