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Laboratory of Protein misfolding diseases study center: systemic amyloidoses

Giampaolo Merlini
Vittorio Perfetti
Laura Obici
Giovanni Palladini

Scientific background
Amyloidoses are protein misfolding diseases caused by more than twenty different proteins with the common feature of forming antiparallel β-sheets organized in fibrils with a characteristic structure evidenced by X ray diffraction and stain properties. Amyloidoses are associated with ageing and underlying degenerative disorders like Alzheimer’s disease, prion diseases and many other acquired and hereditary disorders. The Policlinico San Matteo Amyloid Center (www.amyloidosis.it) is a national referral center and coordinates the Italian Amyloidosis Study Group. Integration of clinical and basic research at this Centre has recently led to the development of new diagnostic and therapeutic tools and to the identification of new mutations responsible for hereditary amyloidosis.
General goals. 1) to define the genetic basis of hereditary amyloidosis; 2) to develop and validate new diagnostic tools in vivo; 3) to develop new drugs; 4) to maintain and organize a biologic specimen bank; 5) to create a national network online, with the aim of gathering clinical and biological data of amyloidosis patients.
Technical skills. The Amyloid Center is able to define the genetic basis of amyloidosis and to characterize germline genes used to synthesize amyloidogenic proteins using molecular biology techniques. Imaging of amyloid deposits in vivo has been established in collaboration with the Nuclear Medicine Unit of the “Fondazione Maugeri”. The Amyloid Center own instruments for protein characterization (chromatographic and electrophoretic systems, mass spectrometry MALDI-TOF) and for evaluation of protein/protein and protein/drug interactions (Biacore).
Research lines. 1. Definition of the genetic basis of systemic and localized amyloidoses. This approach has led to the identification of novel mutations and to the definition of new molecular mechanisms for amyloidogenesis (in collaboration with Prof. Bellotti-Stoppini Unit). 2. Study of germline genes usage in the synthesis of amyloidogenic monoclonal immunoglobulin light chains. This research line has already led to the discovery of genes associated to amyloidogenic light chains organ affinity. Light chains generated by the λ 6a gene have a particular tropism for the kidney and are usually associated with a good prognosis. Studies are under way to identify genes associated with heart involvement which is the main cause of death in amyloid patients. 3. Definition of the molecular basis of organ tropism and tissue damage induced by amyloid proteins. We aim to define the molecular mechanisms (receptors, receptor/oligomer interaction) that underlie organ tropism and cytotoxicity of soluble oligomers generated in the early phases of the fibrillogenesis process. This line will be developed together with Prof. Govoni’s unit. 4. Study of amyloid deposits in vivo. After development of an original imaging system of amyloid deposits with tecnetium-labeled aprotinin (a bovine-derived protease inhibitor), we aim to identify and study synthetic analogues of aprotinin with the same affinity to amyloid. This project relies on the collaboration of a biotechnology firm (Tecnogen, Caserta) and has obtained support from the Italian Ministry of Health.
Technological perspective of the research. The knowledge on the molecular mechanisms underlying amyloid protein organ tropism and damage will be integrated with that gained by Prof. Bellotti’s and Prof. Govoni’s units in order to design, produce and test a new generation of drugs for amyloid treatment. Moreover, strictly cooperating with biotechnology industry (Tecnogen), new molecules for the imaging of amyloid deposits will be developed.

Department of Biochemistry
Faculty of Medicine
Via Taramelli, 3/b Pavia
Tel. 0382.502994
e-mail: gmerlini@smatteo.pv.it


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