Work in our laboratory covers a wide spectrum of topics related to prions and amyloids, across physiology and disease. We investigate these phenomena by employing a variety of chemical, biochemical, biophysical, cellular and animal technologies, with the ultimate objective of defining novel therapeutic approaches for neurodegenerative diseases.
A brief introduction to prions and amyloids. Aging is intrinsically linked to a broad range of molecular, cellular and functional changes, which particularly affect the integrity of the nervous system. One fundamental process altered by aging is protein folding. When proteins misfold, they acquire alternative conformations capable of seeding a cascade of molecular events, ultimately resulting in neuronal dysfunction and death. Indeed, a wide range of age-related disorders is linked to the accumulation in the brain of insoluble protein aggregates, often called amyloids. Examples include common disorders such as Parkinson’s and Alzheimer’s disease, as well as rarer disorders such as Amyotrophic lateral sclerosis (ALS) and prion diseases. The latter are among the most unusual and fascinating pathologies linked to protein misfolding, and are caused by the conformational conversion of the cellular prion protein (PrPC), an endogenous cell-surface glycoprotein, into a misfolded isoform, called PrPSc, that accumulates in the central nervous system of affected individuals. PrPSc is an infectious protein (prion), lacking information-coding nucleic acids, which replicates by directly binding to PrPC, and triggering its conformational rearrangement into new PrPSc molecules.
The main lines of investigation currently ongoing in our lab are as follow:
- Targeting the cellular prion protein to halt neurodegeneration
Enormous efforts have been expended by academic laboratories and pharmaceutical companies worldwide to understand the key pathogenic events that lye at the root of neurodegenerative diseases. Association studies are drawing unexpected correlations between different neurodegenerative diseases, and suggesting that the pathological processes underlying these disorders may converge on few molecular hubs. We believe that PrPC is one of such factors, by acting as a transducer of neurotoxicity for various pathogenic protein aggregates, including its own misfolded state (PrPSc), as well as toxic oligomers of the amyloid beta (Aβ) peptide, which are associated with Alzheimer’s disease. Our lab is exploring a cross-disciplinary approach of biochemical pharmacology to understand the biology of PrPC, and design novel pharmacological agents to stop its toxicity-transducing activity.
See also Dulbecco Telethon Institute, Lab Biasini @: https://dti.telethon.it/
Developing new tools to study protein misfolding
Recent evidence suggests that the pathogenic mechanisms operating in prion diseases may lie at the root of the neurodegenerative processes occurring in several other disorders. In fact, misfolded protein isoforms that accumulate in these diseases have been shown to possess prion-like, self-templating properties, which could explain their spreading in different brain regions, as well as their toxicity. We are currently developing novel cellular assays to study the generation, propagation and toxicity of prions and amyloids in petri dishes.
Identifying physiological roles for protein misfolding in extreme biological conditions
Mounting evidence indicates that some of the pathological pathways occurring in neurodegenerative diseases could operate physiologically in extreme biological contexts, such as hibernation. For example, the thirteen-lined ground squirrel, a natural hibernator endemic of North America, manifests a form of regulated neurodegeneration during torpor, associated with the hyperphosphorylation of the microtubule-associated protein tau, and loss of synaptic endings in specific brain areas. Intriguingly, these phenotypes are fully reversed upon restoration of normal body temperature. These observations suggest that neurodegeneration-like mechanisms, including protein misfolding and aggregation, could be encoded in the functional repertoire of the hibernating mammalian brain. By employing cell and animal models of hibernation, we try to investigate the potential role of prions and amyloids in the biological adaptation to extreme biological conditions.
- Emiliano Biasini, PI
- Tania Massignan, postdoctoral Fellow
- Silvia Biggi, PhD student
- Giovanni Spagnolli, PhD student
- Caterina Ciani, PhD student
- Giulia Maietta, Pre-doc Fellow
- Marta Rigoli, QCB Master student
- Maria Letizia Barreca, Giuseppe Manfroni, Stefano Sabatini & Violetta Cecchetti, University of Perugia, ITALY
- Pietro Faccioli & Carlo Musio, University of Trento, ITALY
- Romolo Nonno, Istituto Superiore di Sanità, ITALY
- Valentina Bonetto, Mario Negri Institute for Pharmacological Research in Milan, ITALY
- Jesús R. Requena, University of Santiago de Compostela, SPAIN
- Joaquin Castilla, CIC-Biogun, SPAIN
- Ina Vorberg, DZNE, Germany
- Steven Collins, University of Melbourne, Australia
Stincardini C, Massignan T, Biggi S, Elezgarai SR, Sangiovanni V, Vanni I, Pancher M, Adami V, Moreno J, Stravalaci M, Maietta G, Gobbi M, Negro A, Requena JR, Castilla J, Nonno R & Biasini E., An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein. PLoS One. 2017 Aug 7;12(8):e0182589. doi:10.1371/journal.pone.0182589.
Massignan T, Sangiovanni V, Biggi S, Stincardini C, Elezgarai SR, Maietta G, Andreev IA, Ratmanova NK, Belov DS, Lukyanenko ER, Belov GM, Barreca ML, Altieri A, Kurkin AV, Biasini E., A novel small molecule inhibitor of prion replication and mutant prion protein toxicity. ChemMedChem. 2017 Jul 19. doi: 10.1002/cmdc.201700302. https://www.ncbi.nlm.nih.gov/pubmed/28722340
Nyeste A, Stincardini C, Bencsura P, Cerovic M, Biasini E, Welker E. The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells. Sci Rep. 2016 Nov 7;6:36441. doi: 10.1038/srep36441 https://www.ncbi.nlm.nih.gov/pubmed/27819308
Elezgarai SR, Biasini E. Common therapeutic strategies for prion and Alzheimer's diseases. Biol Chem. 2016 Nov 1;397(11):1115-1124. doi: 10.1515/hsz-2016-0190. https://www.ncbi.nlm.nih.gov/pubmed/27279060
Massignan T, Cimini S, Stincardini C, Cerovic M, Vanni I, Elezgarai SR, Moreno J, Stravalaci M, Negro A, Sangiovanni V, Restelli E, Riccardi G, Gobbi M, Castilla J, Borsello T, Nonno R, Biasini E. A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein. Sci Rep. 2016 Mar 15;6:23180. doi: 10.1038/srep23180. https://www.ncbi.nlm.nih.gov/pubmed/26976106
Iraci N, Stincardini C, Barreca ML and Biasini E. Decoding the function of the N-terminal tail of the cellular prion protein to inspire novel therapeutic avenues for neurodegenerative diseases. Virus Res. 2014 Oct 23. http://www.ncbi.nlm.nih.gov/pubmed/25456402
Biasini E, Unterberger U, Solomon IH, Massignan T, Senatore A, Bian H, Voigtlaender T, Bowman FP, Bonetto V, Chiesa R, Luebke J, Toselli P and Harris DA. A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J Neurosci. 2013 Feb 6;33(6):2408-18. http://www.ncbi.nlm.nih.gov/pubmed/23392670
Fluharty BR, Biasini E, Stravalaci M, Sclip A, Diomede L, Balducci C, La Vitola P, Messa M, Colombo L, Forloni G, Borsello T, Gobbi M, Harris DA. An N-terminal fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity in vivo. J Biol Chem. 2013 Mar 15;288(11):7857-66. http://www.ncbi.nlm.nih.gov/pubmed/23362282
Biasini E, Turnbaugh JA, Massignan T, Veglianese P, Forloni G, Bonetto V, Chiesa R and Harris DA. The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells. PLoS One 2012. 2012;7(3):e33472. http://www.ncbi.nlm.nih.gov/pubmed/22428057
Biasini E, Turnbaugh JA, Unterberger U, Harris DA. Prion protein at the crossroads of physiology and disease. Trends Neurosci. 2012 Feb;35(2):92-103. http://www.ncbi.nlm.nih.gov/pubmed/22137337
For a complete list: https://www.ncbi.nlm.nih.gov/pubmed/?term=emiliano+biasini