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Ricerca Gruppi di ricerca e contributi alla ricercaThe Section of BiochemistryGruppo Chiti

Laboratory for the Study of Protein Misfolding Diseases

Name of Research Team/Laboratory

Laboratory for the study of protein misfolding diseases


Coordinator

Name                                                              Fabrizio Chiti

Position                                                          Full Professor of Biochemistry

e-mail:                                                            fabrizio.chiti@unifi.it

telephone number                                           +39-055-2751220

    

 

Brief biographical sketch of the Coordinator

Fabrizio Chiti received his Master Degree (M.Sc.) in Biological Sciences at the University of Florence in Italy and his PhD (D.Phil) in Chemistry at the University of Oxford. His research, performed under the supervision of Prof. C.M. Dobson, concerned protein folding studies. His post-doctoral work, performed in the field of protein aggregation and amyloid formation, was carried out at the University of Florence for 2 years and at the University of Cambridge for 1 year. He was Associate Professor from 2002 to 2010 and is now Full Professor of Biochemistry at the University of Florence.

 

Member of the scientific board of the Doctorate/PhD Program in

Biomedical Sciences, Coordinator

 

Member of the following Scientific Societies

  • Academia Europaea, member by appointment
  • Sigma Xi Honor Society, member by appointment
  • American Society for Biochemistry and Molecular Biology (ASBMB), editorial board member by appointment
  • Associazione Italiana sulla Ricerca Alzheimer (AIRAlzh), CTS coordinator
  • Italian Society of Biochemistry (SIB)
  • Protein Society (PS)
  • Society for Neuroscience (SfN)

Member of the editorial board of the following Journals

  • Journal of Biological Chemistry
  • Protein Engineering Design and Selection
  • Frontiers in Molecular Biosciences

 

Research Team

 

Current research interests 

Proteins have a generic tendency to convert from their soluble states into misfolded states, often leading to insoluble highly structured aggregates known as amyloid fibrils. Since these aggregates are deleterious to the cells, especially in the form of early forming oligomers, the cellular machinery has evolved, among other requirements, to inhibit uncontrolled protein aggregation. Failure to inhibit protein aggregation often results in pathology. To date, a large number of very diverse human diseases, including Alzheimer’s, Parkinson’s disease, type II diabetes, Fabry disease, cystic fibrosis, Charcot-Marie-Tooth disease, have been recognised to be associated with protein misfolding, often with the formation of amyloid fibrils or protein inclusions with amyloid-like properties.

The research of this lab uses a multi angle approach to investigate the mechanisms by which soluble proteins assemble into ordered aggregates and by which the resulting aggregates cause cell dysfunction. Examples of past and ongoing projects are listed below:

  • Study, at a molecular level, of the process by which native proteins convert into misfolded states necessary to initiate aggregation or undergo native-like aggregation
  • Study, in molecular depth, of the conversion of fully or misfolded states of proteins into amyloid fibrils and their precursor oligomers
  • Study of the relationship between structure and cellular toxicity of protein oligomers
  • Editing of mathematical algorithms able to predict fundamental aspects of protein aggregation in vitro and in vivo
  • Protein folding, misfolding, aggregation and cell toxicity in Alzheimer, Parkinson, amyotrophic lateral sclerosis, ATTR, Charcot-Marie-Tooth diseases
  • Purification of full-length and individual domains of TDP-43 and study of its liquid-liquid phase separation (LLPS) and aggregation
  • Biophysical and toxicity analysis of cerebrospinal fluid (CSF) samples from Alzheimer patients
  • Interaction of steroid polyamines of pharmacological relevance with liposomes and cell membranes
  • Reaction of proteostasis to protein misfolding and aggregation
  • Investigation of molecular chaperones and mall molecules as inhibitors of the toxicity of protein oligomers

 

The research activity relies on a number of national and world-wide collaborations with well established groups. In addition to classical molecular biology and biochemical techniques for manipulation of genes and purification of their resulting proteins, the experimental work involves the utilisation of biophysical techniques for the characterisation of the folding and aggregation processes. These include turbidimetry, fluorescence, circular dichroism and Fourier-transform infra-red spectroscopies, static and dynamic light scattering, microfluidics, plate readers, stopped-flow devices and electron microscopy. Infrastructures for protein engineering and the high-throughput purification of protein variants are available. Studies of the interaction of protein aggregates with cells are based on the utilization of cell cultures and specific protocols to assess their viability, oxidative stress and calcium homeostasis. Confocal microscopy, FACS, and superresolution STED microscopy are widely used. Many other techniques are feasible through established collaborations, such as NMR, TEM, AFM, SAXS, cryo-EM, MD simulations, etc.

 

Current / recent sources of funding (years 2011-2021)

  • Rientro Cervelli Rita Levi Montalcini, Bando 2011
  • AriSLA, Bando 2011
  • MIUR, FIRB Futuro in ricerca 2012
  • Cassa di Risparmio di Pistoia e Pescia 2014
  • Regione Toscana, Bando FAS-salute 2015
  • Finanziamenti ELAN 2015 (collaboraz. con Università di Cambridge)
  • EC commission, N2B Patch 2016
  • Cassa di Risparmio di Firenze, Bando 2016
  • AriSLA, Bando 2017
  • ANVUR, FFABR 2017
  • Dip. Eccellenza (Gender medicine) 2018
  • Regione Toscana, bando FAS-salute 2018
  • CRF/UNIF, Bando Malattie Neurodegenerative 2018
  • MIUR, PRIN 2020
  • CRF/UNIF, Bando Malattie Neurodegenerative 2021
  • Fondi di Ateneo

 

10 best publications (years 2016-2021)

  1. Perni M, Galvagnion C, Maltsev A, Meisl G, Müller MB, Challa PK, Kirkegaard JB, Flagmeier P, Cohen SI, Cascella R, Chen SW, Limboker R, Sormanni P, Heller GT, Aprile FA, Cremades N, Cecchi C, Chiti F, Nollen EA, Knowles TP, Vendruscolo M, Bax A, Zasloff M, Dobson CM. (2017). A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proc. Natl. Acad. Sci. USA. 114, E1009-E1017. IF 10.700
  2. Fusco G, Chen SW, Williamson PTF, Cascella R, Perni M, Jarvis JA, Cecchi C, Vendruscolo M, Chiti F, Cremades N, Ying L, Dobson CM, De Simone A. (2017). Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers. Science 358:1440-1443. IF 47.728
  3. Chiti F, Dobson CM. (2017). Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu. Rev. Biochem. 86, 27-68. IF 23.643
  4. D'Andrea C, Foti A, Cottat M, Banchelli M, Capitini C, Barreca F, Canale C, de Angelis M, Relini A, Maragò OM, Pini R, Chiti F, Gucciardi PG, Matteini P. Small. (2018). Nanoscale Discrimination between Toxic and Nontoxic Protein Misfolded Oligomers with Tip-Enhanced Raman Spectroscopy. Small 14, e1800890. IF 13.281
  5. Limbocker R, Chia S, Ruggeri FS, Perni M, Cascella R, Heller GT, Meisl G, Mannini B, Habchi J, Michaels TCT, Challa PK, Ahn M, Casford ST, Fernando N, Xu CK, Kloss ND, Cohen SIA, Kumita JR, Cecchi C, Zasloff M, Linse S, Knowles TPJ, Chiti F, Vendruscolo M, Dobson CM (2019). Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes. Nature Commun. 10:225. IF 14.919
  6. Errico S, Lucchesi G, Odino D, Muscat S, Capitini C, Bugelli C, Canale C, Ferrando R, Grasso G, Barbut D, Calamai M, Danani A, Zasloff M, Relini A, Caminati G, Vendruscolo M, Chiti F (2020). Making biological membrane resistant to the toxicity of misfolded protein oligomers: a lesson from trodusquemine. Nanoscale 12:22596-22614. IF 7.790
  7. Ghadami SA, Chia S, Ruggeri FS, Meisl G, Bemporad F, Habchi J, Cascella R, Dobson CM, Vendruscolo M, Knowles TPJ, Chiti F (2020). Transthyretin Inhibits Primary and Secondary Nucleations of Amyloid-β Peptide Aggregation and Reduces the Toxicity of Its Oligomers. Biomacromolecules 21, 1112-1125. IF 7.020
  8. Cascella R, Chen SW, Bigi A, Camino JD, Xu CK, Dobson CM, Chiti F, Cremades N, Cecchi C (2021). The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells. Nature Commun. 12:1814. IF 14.919
  9. Capitini C, Fani G, Vivoli Vega M, Penco A, Canale C, Cabrita LD, Calamai M, Christodoulou J, Relini A, Chiti F (2021). Full-length TDP-43 and its C-terminal domain form filaments in vitro having non-amyloid properties. Amyloid. 28, 56-65. IF 7.141
  10. Limbocker R, Errico S, Barbut D, Knowles TPJ, Vendruscolo M, Zasloff M, Chiti F (2021). Squalamine and trodusquemine: two natural products for neurodegenerative diseases, from physical chemistry to the clinic. Nat prod. Rep. published online. IF 13.423

 

Main scientific contributions

  • Editing of computational tools for the prediction of protein aggregation
  • Identification of two structural/morphological determinants of protein oligomer toxicity
  • Characterisation of the toxicity cascade associated with protein misfolded oligomers
  • Identification of a novel function of molecular chaperones: inhibition of protein oligomer toxicity
  • Characterisation, at the molecular level, of the process of native-like aggregation
  • Elucidation of whether protein disorders associated with TDP-43 aggregation consist of gain-of-function or loss-of function diseases
  • Clarification of the pathogenicity of profiln-1 mutations associated with a familial form of amyotrophic lateral sclerosis
  • Identification and mechanism of action of squalamine and trodusquemine as promising drugs against neurodegenerative disease
  • Purification and analysis of TDP-43

 

Collaborations

  • Prof. Christopher M. Dobson, Department of Chemistry, University of Cambridge, UK
  • Prof. Michele Vendruscolo, Department of Chemistry, University of Cambridge, UK
  • Prof. Tuomas Knowles, Department of Chemistry, University of Cambridge, UK
  • Prof. Michael Zasloff and Denise Barbut, Enterin Inc, Philadelphia
  • Prof. Mark Wilson and Heath Ecroyd, School of Biological Sciences, University of Wollongong, Australia 
  • Prof. Jeff Kelly, Department of Molecular and Experimental Medicine, The Scripps Research Institute
  • Prof. Alfonso De Simone, Department of Life Sciences, Imperial College London, UK
  • Cintia Roodveldt, Andalusian Center for Molecular Biology and Regenerative Medicine, University of Seville, Spain
  • Prof. Ramon A. Alvarez-Puebla, Universitat Rovira i Virgili & Center for Chemical Technology of Catalonia, Tarragona, Spain
  • Dr Nunilo Cremades, Universitat de Saragoza, Spain
  • Prof. Ali A. Moosavi-Movahedi, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
  • Prof. Khosro Khajeh, Department of Biochemistry, Tarbiat Modares University, Tehran, Iran
  • Prof. Hassan Ramshini, Department of Biology, Payam e Noor University, Branch of Sabzevar, Iran
  • Prof. Neville Vassallo, Department of Physiology & Biochemistry, University of Malta, Tal-Qroqq, Malta
  • Prof. Annalisa Relini, Dipartimento di Fisica, Università di Genova, Italy
  • Prof. Alessandra Corazza, Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Italy
  • Prof. Martino Bolognesi and Prof. Stefano Ricagno, Dipartimento di Bioscienze, Università di Milano, Italy
  • Paolo Matteini, Istituto di Fisica Applicata, Consiglio Nazionale delle Ricerche, Sesto Fiorentino, Italy.
  • Prof. Angelo Poletti, Dipartimento di Scienze Farmacologiche e Biomolecolari,
Università degli Studi di Milano, Italy
  • Prof. Daniela Marasco, Dipartimento di Farmacia, Università di Napoli Federico II, Italy
  • Prof. Stefano Gianni, Dipartimento di Scienze Biochimiche, University of Rome La Sapienza, Italy
  • Prof. Katia Cortese, Dipartmento di Fisica, Univeristà di Genova

 

Ultimo aggiornamento

14.01.2022

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