V. Bellotti
From the molecular basis to the therapy of Systemic Amyloidosis
Group members
- Vittorio Bellotti (coordinator- vbellot@unipv.it)
- Monica Stoppini (stoppini@unipv.it)
- Patrizia Mangione (p.mangione@unipv.it).
- Sofia Giorgetti (s.giorgetti@unipv.it)
- Maurizia Valli (maurizia.valli@unipv.it)
- Sara Raimondi ( sara.raimondi@unipv.it)
- Loredana Marchese (loredana.marchese@unipv.it)
- Irene Zorzoli (irene.zorzoli@unipv.it)
- Angelo Gallanti (angelo.gallanti@unipv.it)
- Patrizia Arcidiaco (patrizia.arcidiaco@unipv.it)
- Riccardo Porcari(r.porcari@ucl.ac.uk)
Gugliemo Verona (g.verona@ucl.ac.uk)
Giulia Faravelli (giulia.faravelli01@universitadipavia.it)
Systemic amyloidosis is a fatal disease caused by misfolding of native globular proteins which then aggregate extracellularly as insoluble fibrils, damaging the structure and function of affected organs. It is responsible for about one per thousand of all deaths in developed countries. The mechanisms that govern the induction, timing, anatomical distribution, progression, clearance and pathological effects of amyloid deposition are still poorly understood. This project aims to elucidate the mechanism of conversion of amyloidogenic globular proteins to fibrils using systems which closely resemble in vivo conditions and to identify biological factors modulating the natural history of the disease. We have recently discovered that biomechanical forces acting at the extracellular space are sufficient to partially unfold and prime the pathological aggregation and that, in several cases, selective proteolytic cleavages by a mechano-enzymatic mechanism are required. Having extensively investigated mechanisms of fibrillogenesis in vitro, we are now ready to generate physiological models of increased complexity. Therefore, the globular to amyloid conversion process will be investigated using biological scaffolds based on normal and/or pathological decellularized tissues and animal models. Transgenic C. elegans strains and mice expressing beta2-m or transthyretin are well established in our laboratory and available to validate putative inhibitors of amyloidogenesis.
Selected papers of the last 5 years
Valleix S, Verona G, Jourde-Chiche N, Nédelec B, Mangione PP, Bridoux F, Mangé A, Dogan A, Goujon JM, Lhomme M, Dauteuille C, Chabert M, Porcari R, Waudby CA, Relini A, Talmud PJ, Kovrov O, Olivecrona G, Stoppini M, Christodoulou J, Hawkins PN, Grateau G, Delpech M, Kontush A, Gillmore JD, Kalopissis AD, Bellotti V. D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile. Nat Commun. 2016 Jan 21;7:10353.
Marcoux J, Mangione PP, Porcari R, Degiacomi MT, Verona G, Taylor GW, Giorgetti S, Raimondi S, Sanglier-Cianférani S, Benesch JL, Cecconi C, Naqvi MM, Gillmore JD, Hawkins PN, Stoppini M, Robinson CV, Pepys MB, Bellotti V. A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis. EMBO Mol Med. 2015 Aug 18;7(10):1337-49.
Stoppini M, Bellotti V. Systemic amyloidosis: lessons from β2-microglobulin. J Biol Chem. 2015 Apr 17;290(16):9951-8.
Mangione PP, Porcari R, Gillmore JD, Pucci P, Monti M, Porcari M, Giorgetti S, Marchese L, Raimondi S, Serpell LC, Chen W, Relini A, Marcoux J, Clatworthy IR, Taylor GW, Tennent GA, Robinson CV, Hawkins PN, Stoppini M, Wood SP, Pepys MB, Bellotti VProteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis. .Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1539-44.
Valleix S, Gillmore JD, Bridoux F, Mangione PP, Dogan A, Nedelec B, Boimard M, Touchard G, Goujon JM, Lacombe C, Lozeron P, Adams D, Lacroix C, Maisonobe T, Planté-Bordeneuve V, Vrana JA, Theis JD, Giorgetti S, Porcari R, Ricagno S, Bolognesi M, Stoppini M, Delpech M, Pepys MB, Hawkins PN, Bellotti V. Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin. N Engl J Med. 2012 Jun 14;366(24):2276-83.
