Laboratory of Protein misfolding diseases study center: systemic amyloidoses
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
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