DIPARTIMENTO DI MEDICINA MOLECOLARE
The aim of the research
Amyloidosis is a serious, usually fatal, disease caused by deposition in the tissues of insoluble fibres formed from some of the body's own proteins.
Although much is known about these proteins, the molecular mechanism that in vivo, leads to the transformation of a globular and functionally active protein into a fibrillar and toxic aggregate is largely unknown. Not knowing what exactly occurs in vivo makes particularly difficult the intelligent design of specific and effective drugs. We have recently discovered a rare form of genetically determined systemic amyloidosis caused by a mutation in the sequence of the ubiquitous β2-m protein. The discovery of the first mutation of β2-m, in which the disease develops without increase in its serum concentration, offered the unique opportunity to exploit our extensive knowledge on structure, misfolding propensity and amyloidogenesis of the wild type protein with emerging comparable data on the variant β2-m. We have now well characterized a partially folded intermediate which can become a target of new drugs and we have established new models in which we could recapitulate the fibrillar conversion of β2-m 1, 5, 6. Three models at increased biological complexity are proposed: 1. A device for monitoring in real time the formation of amyloid fibrils under a controlled flow of a physiological fluid. 2. An invertebrate animal model offering the simplest level of complexity in which however the target tissues of amyloid deposition are represented. 3. A mouse model expressing the amyloidogenic human β2-m that might represent the first mammalian animal model of the disease. With these tools we will study the potential pharmaceutical properties of three different types of amyloid inhibitors including tetracycline analogues, chaperones and antibodies, and will offer fundamental preclinical elements for a rationale medical application.