Overview

Our laboratory is fascinated by the complexity and dynamics of proteins. We investigate the topic by integrating various computational, chemical, biophysical, biochemical, and cellular technologies, with the ultimate objective of defining novel therapeutic approaches for neurodegenerative diseases.

Research directions

The laboratory currently focuses on two main lines of investigation:

  • Define new interdisciplinary approaches to study protein regulation, folding & misfolding
    Aging is intrinsically linked to a broad range of molecular, cellular, and functional changes, which mainly 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, 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 conditions such as Parkinson’s and Alzheimer’s disease and rarer disorders like Amyotrophic lateral sclerosis and prion diseases. Our laboratory combines computational and experimental schemes to study protein regulation, folding, and misfolding in health and disease. Such an integrative approach revealed unexpected principles underlying proteins’ homeostasis by expanding the range of functional conformations that proteins may adopt. Structure of a folding intermediate of the cellular prion protein. The box highlights the residues defining a druggable pocket on such intermediate.

  • Develop new drug discovery paradigms for neurodegenerative disorders.
    Prion diseases are among the most unusual 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) that replicates by directly binding to PrPC and templating its conformational rearrangement into new PrPSc molecules. Academic laboratories and pharmaceutical companies worldwide have expended enormous efforts to understand the key pathogenic events at the root of neurodegenerative diseases. Genomic association studies have drawn unexpected correlations between different neurodegenerative disorders, suggesting that pathological processes may converge on few molecular hubs. We believe that PrPC is one of such factors, as the protein can act as a transducer of neurotoxicity for various pathogenic protein aggregates. Accordingly, our group is currently exploring non-canonical experimental paradigms to suppress the expression of PrPC. Model explaining the mechanism underlying the Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT) method, a novel drug discovery paradigm to post-translationally silence target proteins (see Spagnolli et al. Comms Bio 2021).

See also Lab Biasini @ Telethon Foundation: https://www.telethon.it/cosa-facciamo/ricerca/ricercatori/emiliano-biasini

Group members

  • Emiliano Biasini, Associate Professor
  • Valerio Bonaldo, PhD student
  • Ilaria Zeni, PhD student
  • Nicole Innocenti, PhD student
  • Laura Copat, Master Student
  • Dino Gasparotto, Master Student

Collaborations

  • Pietro Faccioli, Graziano Lolli & Ines Mancini, University of Trento, ITALY
  • Maria Letizia Barreca, Giuseppe Manfroni & Francesca Fallarino, University of Perugia, ITALY
  • Jesús R. Requena, University of Santiago de Compostela, SPAIN
  • Romolo Nonno, Istituto Superiore di Sanità, ITALY
  • Ina Vorberg, DZNE, GERMANY
  • Steven J. Collins, University of Melbourne, AUSTRALIA
  • Mario Salmona, Luisa Diomede, Valentina Bonetto & Giovanni Nardo, Mario Negri Institute for Pharmacological Research in Milan, ITALY

Selected publications

Spagnolli G, Massignan T, Astolfi A, Biggi S, Rigoli M, Brunelli P, Libergoli M, Ianeselli A, Orioli S, Boldrini A, Terruzzi L, Bonaldo V, Maietta G, Lorenzo NL, Fernandez LC, Codeseira YB, Tosatto L, Linsenmeier L, Vignoli B, Petris G, Gasparotto D, Pennuto M, Guella G, Canossa M, Altmeppen HC, Lolli G, Biressi S, Pastor MM, Requena JR, Mancini I, Barreca ML, Faccioli P, Biasini E. Pharmacological inactivation of the prion protein by targeting a folding intermediate. Commun Biol. 2021 Jan 12;4(1):62. doi: 10.1038/s42003-020-01585-x.
https://pubmed.ncbi.nlm.nih.gov/33437023/

Astolfi A., Spagnolli G., Biasini E., Barreca M. L. The Compelling Demand for an Effective PrPC-Directed Therapy against Prion Diseases. ACS MEDICINAL CHEMISTRY LETTERS, vol. 11, p. 2063-2067, ISSN: 1948-5875, doi: 10.1021/acsmedchemlett.0c00528
https://pubmed.ncbi.nlm.nih.gov/33209189/

Spagnolli G, Requena JR, Biasini E.Understanding prion structure and conversion. Prog Mol Biol Transl Sci. 2020;175:19-30. doi: 10.1016/bs.pmbts.2020.07.005.
https://pubmed.ncbi.nlm.nih.gov/32958233/

Manni G, Lewis V, Senesi M, Spagnolli G, Fallarino F, Collins SJ, Mouillet-Richard S, Biasini E. The cellular prion protein beyond prion diseases. Swiss Med Wkly. 2020 Apr 24;150:w20222. doi: 10.4414/smw.2020.20222. PMID: 32330284.
https://pubmed.ncbi.nlm.nih.gov/32330284/

Biggi S, Pancher M, Stincardini C, Luotti S, Massignan T, Dalle Vedove A, Astolfi A, Gatto P, Lolli G, Barreca ML, Bonetto V, Adami V, Biasini E. Identification of compounds inhibiting prion replication and toxicity by removing PrPC from the cell surface. J Neurochem. 2020 Jan;152(1):136-150. doi: 10.1111/jnc.14805. Epub 2019 Jul 18. PMID: 31264722.
https://pubmed.ncbi.nlm.nih.gov/31264722/

Spagnolli G, Rigoli M, Orioli S, Sevillano AM, Faccioli P, Wille H, Biasini E. & Requena JR. Full atomistic model of prion structure and conversion. PLOS Pathogens. 2019; doi:10.1371/journal.ppat.1007864
https://pubmed.ncbi.nlm.nih.gov/31295325/

Rigoli M, Spagnolli G, Faccioli P, Requena JR & Biasini E. Ok Google, how could I design therapeutics against prion diseases? Curr Opin Pharmacol. 2019 May 3;44:39-45. doi: 10.1016/j.coph.2019.03.015.
https://www.ncbi.nlm.nih.gov/pubmed/31059982/

Biasini E. A designer chaperone against prion diseases. Nat Biomed Eng. 2019 Mar;3(3):167-168. doi: 10.1038/s41551-019-0367-6.
https://www.ncbi.nlm.nih.gov/pubmed/30948815/

Barreca ML, Iraci N, Biggi S, Cecchetti V, Biasini E. Pharmacological Agents Targeting the Cellular Prion Protein. Pathogens. 2018 Mar 7;7(1). pii: E27. doi: 10.3390/pathogens7010027.
https://www.ncbi.nlm.nih.gov/pubmed/29518975/

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/

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/

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/

For a complete list (almost): https://www.ncbi.nlm.nih.gov/pubmed/?term=emiliano+biasini