Overview
Work in our laboratory covers a broad spectrum of topics related to protein dynamics across physiology and disease. We investigate these phenomena by integrating various computational, chemical, biophysical, biochemical and cellular technologies, aiming to capitalize on such information to develop new experimental therapies for neurodegenerative diseases.
Research directions
Protein expression and function in eukaryotic cells are tightly harmonized processes modulated by the combination of different layers of regulation, including transcription, processing, stability, and translation of messenger RNA, as well as assembly, maturation, sorting, recycling, and degradation of polypeptides. Integrating all these pathways and the protein quality control machinery, deputed to avoid the production and accumulation of aberrantly folded proteins, determines protein homeostasis. Over the last decade, the combined development of accurate time-resolved experimental techniques and efficient computer simulations has opened the possibility of investigating biological mechanisms at atomic resolution with physics-based models. A meaningful example is the reconstruction of protein folding pathways at atomic resolution, which has enabled the characterization of the folding kinetics of biologically relevant globular proteins. Combining these innovative computational technologies with rigorous experimental approaches reveals the existence of non-native metastable states transiently appearing along the folding process of such proteins. We are primarily interested in testing the possibility that such protein folding intermediates could play roles in disparate biological processes, from the post-translational regulation of protein expression to disease-relevant protein misfolding mechanisms. We also aim to exploit the information encoded into protein folding pathways to design an entirely new generation of pharmacological agents capable of promoting the selective degradation of protein targets.
The image illustrates the rationale underlying the PPI-FIT (Pharmacological Protein Inactivation by Folding Intermediate Targeting) paradigm. Polypeptides exiting the ribosomal channel start the folding process. Folding intermediates transiently appearing along this process could be targeted with small molecules binding to unique pockets on their surface. Such a binding event ultimately interferes with the protein folding process, prompting the quality control machinery of the cells to reroute the polypeptide to degradation pathways. The technology is currently exploited by Sibylla Biotech (www.sibyllabiotech.it).
The patch of the Zeprion-2 space mission. The experiment aims at performing the crystallization of the prion protein on the International Space Station using a remotely controlled microfluidic device. The mission builds on the hypothesis that the absence of convective motion, as obtained in microgravity conditions, could prevent protein aggregation and favor crystallization. The experiment is made possible by the collaboration with the company SpacePharma (https://www.spacepharma.health/) and it is supported by the Business in Space Growth Network (BSGN) program of the European Space Agency (ESA, https://bsgn.esa.int/)
Our lab has developed an innovative high content screening platform called LIPS (Light Identification of Protein Suppressors) to identify compounds that lower PrP levels. By screening over 2,000 drugs, we found that cardiac glycosides potently reduce PrP expression, a result confirmed by different orthogonal techniques. Based on these findings, the local ethics committee has approved the Brainheart observational clinical study to assess whether the same effect occurs in humans, an important step toward translating our discoveries into new therapeutic opportunities for prion and related neurodegenerative diseases.
We recently described a class of phosphorylation sites, named cryptic phosphosites, buried within protein cores. Their transient exposure during folding suggests a novel regulatory mechanism linking co-translational phosphorylation to protein folding regulation (https://darkphosphoproteome.com/)
JOIN OUR TEAM!
If you're a student at the bachelor, master or doctoral level, or a researcher at postdoctoral level, and you possess a strong interest in protein biology and experimental drug discovery, then our group might be the perfect fit for you. Protein dynamics is a complex process, and tackling it requires a broad range of scientific approaches. In our laboratory, you will have the opportunity to work with a team of researchers from highly diverse scientific backgrounds, gaining exposure to fields like computational biophysics, theoretical and synthetic chemistry, biochemistry and cell biology. By training with us, you will develop a deep understanding of the molecular mechanisms involved in protein folding and misfolding and have the opportunity to use advanced techniques to probe this process and discover new drugs for neurological disorders. By joining us, you will also be part of a vibrant community of scientists who are passionate about their work. You'll have the opportunity to participate in regular research meetings, conferences, and seminars, which will help you develop a broad network of colleagues and collaborators.
Group members
- Emiliano Biasini, Associate Professor
- Sacha Genovesi, Lab Manager
- Ilaria Zeni, Postdoctoral Fellow
- Nicole Innocenti, Postdoctoral Fellow
- Giorgia Giovannini, Marie Curie Fellow
- Dino Gasparotto, PhD Student
- Elisa Nicolini, PhD Student
- Almog Levi, PhD Student
- Chiara Vecchi, PhD Student
- Annarita Zanon, Visiting PhD Student
Collaborations
- Ines Mancini, Graziano Lolli, Alberto Inga & Yari Ciribilli, University of Trento, ITALY
- Pietro Faccioli, University of Milano-Bicocca, ITALY
- Maria Letizia Barreca, Giuseppe Manfroni & Francesca Fallarino, University of Perugia, ITALY
- Jesús R. Requena, University of Santiago de Compostela, SPAIN
- Romolo Nonno, Ilaria Vanni, Patrizia Ratano & Claudia D’Agostino, Istituto Superiore di Sanità, Rome, ITALY
- Roman Polishchuk, Raffaella Petruzzelli & Carmine Settembre, TIGEM, Naples, ITALY
- Pietro Roversi, CNR, ITALY
- Giovanni Nardo & Valentina Bonetto, Mario Negri Institute in Milan, ITALY
- Alan Ianeselli, Yale University, USA
Industrial Collaborations
Funding
Bando: PRIN 2022 (D.D. 104/22)
Non-canonical small molecule degraders of the prion protein to treat neurodegenerative disorders
Emiliano Biasini, Responsabile di Unità
Codice Protocollo: 2022PP8WNZ CUP: E53D23009460006
Selected publications
Zeni I, Innocenti N, Gasparotto D, Berti G, Nicolini E, Pancher M, Mattè A, Gatto P, Sidarovich V, Vecchi C, Libergoli M, Granzotto I, Righi D, Schmitt-Ulms G, Adami V, Biasini E. A Bimolecular Fluorescence Complementation Assay for the Rapid Identification of Compounds Suppressing the Cellular Prion Protein. Sneak Peek, Cell Chem. Biol. 2025.
http://dx.doi.org/10.2139/ssrn.5381847
Gasparotto D, Zanon A, Bonaldo V, Marchiori E, Casagranda M, Di Domenico E, Copat L, Fortunato Asquini T, Rigoli M, Feltrin SV, Lopez Lorenzo N, Lolli G, Pennuto M, Requena JR, Rota Stabelli O, Minervini G, Micheletti C, Spagnolli G, Faccioli P, Biasini E. Mapping Cryptic Phosphorylation Sites in the Human Proteome. EMBO J. 2025 Oct 3. doi: 10.1038/s44318-025-00567-1.
https://pubmed.ncbi.nlm.nih.gov/41044218/
Barreca ML, Biasini E. Therapeutic Trajectories in Human Prion Diseases. Subcell Biochem. 2025:112:91-113. PMID: 41004055 DOI: 10.1007/978-3-031-97055-9_5.
https://pubmed.ncbi.nlm.nih.gov/41004055/
Innocenti N., Tähtinen P., Spagnolli G., Perrucci C., Bellini M., Parolin E., Bonaldo V., Biasini E., Mancini I. Enantiomers of the prion protein degrader SM875: production and configurational assignment, in silico analysis and in vitro evaluation. Bioorg Chem. 2025 Jul 1;161:108489. doi: 10.1016/j.bioorg.2025.108489.
https://pubmed.ncbi.nlm.nih.gov/40286470/
Petruzzelli R, Catalano F, Crispino R, Polishchuk EV, Elia M, Masone A, Lavigna G, Grasso A, Battipaglia M, Sepe LV, Akdogan B, Reinold Q, Del Prete E, Carrella D, Torella A, Nigro V, Caruso E, Innocenti N, Biasini E, Puchkova L, Indrieri A, Ilyechova EY, Piccolo P, Zischka H, Chiesa R, Polishchuk R. Prion protein promotes copper toxicity in Wilson disease. Nat Commun. 2025 Feb 8;16(1):1468. doi: 10.1038/s41467-025-56740-x
https://pubmed.ncbi.nlm.nih.gov/39922819/
Biasini E, Faccioli P. Functional, Pathogenic, and Pharmacological Roles of Protein Folding Intermediates. Proteins. 2023 Feb 13. doi: 10.1002/prot.26479.
https://pubmed.ncbi.nlm.nih.gov/36779817/
Spagnolli G, Massignan T, et al. 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/
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.
https://pubmed.ncbi.nlm.nih.gov/32330284/
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 Pathog. 2019 Jul 11;15(7):e1007864. 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.
pubmed.ncbi.nlm.nih.gov/31059982/?fromterm=emiliano+biasini&fromsort=date&frompos=4
Biasini E. A designer chaperone against prion diseases. Nat Biomed Eng. 2019 Mar;3(3):167-168. doi: 10.1038/s41551-019-0367-6.
pubmed.ncbi.nlm.nih.gov/30948815/?fromterm=emiliano+biasini&fromsort=date&frompos=5