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Protein misfolding and aggregation in neurodegenerative diseases

Team leader : Ronald MELKI (Research director CNRS)

Published on 15 January 2021
R Melki.jpg


 Ronald MELKI

Research focus

The accumulation of protein aggregates within the central nervous system is the hallmark of several progressive neurodegenerative disorders (e.g. Alzheimer, Parkinson, Huntington and or multiple system atrophy). These aberrant protein conformers are the consequence of the misfolding and aggregation of specific proteins. The protein aggregates that are tightly associated to neurodegenerative disease are able to spread from cell to cell in the brain in a prion-like manner. These abnormal proteins replicate and trigger the progressive and irreversible neurodegeneration of cells in the brain.

At the molecular level, these abnormal and toxic proteins exist as fibrillar structures. We demonstrated that a given protein can acquire different fibrillar structures named conformational polymorphs. These polymorphs spread and template the aggregation of healthy proteins within cells. The resulting aggregates possess similar morphological and pathological characteristics as the original polymorph. Thus, they form pathological strains with distinct characteristics that could trigger or contribute to the clinical heterogeneity of different neurodegenerative diseases involving the same protein.

Objectives of the team

  • Decipher the molecular events leading to the aggregation of polypeptides that propagate from one cell to another and amplify by recruiting the soluble form of their constituting polypeptides, 
  • Document the role of the players that maintain protein homeostasis within the cells, as the protein aggregates we are interested in form upon proteostasis impairment,
  • Characterize the structure of different fibrils produced in vitro and derived from human samples, determine their “functional” properties,
  • Develop different approaches to prevent the aggregation and propagation of pathological proteic strains.

Methods and expertise

  • Protein expression (in bacteria and yeast) and purification ;
  • Assembling pathological forms of the proteins, amplification of pathological proteins from patients samples; cell culture, including primary neuronal cells); 
  • Site directed mutagenesis and protein labeling ;
  • Thermodynamic and kinetic  methods of protein-protein interaction and self-assembly ;
  • Spectroscopy (UV, visible, IR, circular dichroism) ;
  • Spectrofluorimetry, fluorescence polarization and light scattering ;
  • Proteomic methods (limited proteolysis, cross-linking, mass spectrometry) ;
  • Mapping of surface interfaces involved in protein-protein interactions (H/D exchange and mass spectrometry) ;
  • Analytical ultracentrifugation ;
  • Confocal and electron microscopy.

Team members 


  • Ania ALIK (Engineer)
  • Tracy BELLANDE (Research technician CNRS)
  • Annabelle BONINO (PhD student CEA, 2020 - 2023)
  • Alexis FENYI (Post-Doctoral fellow)
  • Alison GERVAIS (Engineer)
  • Maud LANDUREAU (PhD student, 2018 - 2021)
  • Karine MADIONA (Engineer, CNRS)
  • Virginie REDEKER (Researcher, INSERM) 
  • Nolwen REY (Researcher, CNRS)
  • Hugo RUBIO (PhD student CEA, 2019 - 2022)

Current fundings 

  1. EU-Joint Program on Neurodegenerative diseases/Agence Nationale de la Recherche : Protecting protein homeostasis in synucleinopathies and tauopathies by modulating the Hsp70/co-chaperone network, PROTEST-70
  2. EU-Joint Program on Neurodegenerative diseases/Agence Nationale de la Recherche : Intraneuronal transport related pathways across neurodegenerative diseases, TransPathND
  3. European Commission, Innovative Medicines Initiative : A quantitative approach towards the characterisation of mitochondrial dysfunction in Parkinson’s Disease, PD-MitoQUANT
  4. Agence Nationale de la Recherche : Development of synuclein model in Macaque, SUMMA - European Commission, Innovative Medicines Initiative: Identification of druggable targets modulating misfolded proteins in Alzheimer’s and Parkinson’s diseases, IMPRIND
  5. Fondation pour la Recherche Médicale : New pathological mechanisms involved in Alzheimer disease, toward innovative therapeutic approaches
  6. France Parkinson : Molecular basis of selective propagation of alpha-synuclein aggregates in the central nervous system in Parkinson’s disease 

Scientific awards

  • Coups d'Elan pour la Recherche Française 2011, Bettencourt Schueller foundation award, Ronald Melki

  • Great scientific prize 2016 from the foundation Simone and Cino Del Duca – Institut de France, Ronald Melki

  • JiePie AWARD 2019 for research on multiple system atrophy, Ronald Melki

External collaborators

  • Pr. Veerle Baekelandt, KU Leuven, Belgium
  • Dr. Anja Böckmann, ENS, Lyon University, France
  • Dr. Luc Buée,, Lille University, France
  • Dr. Michel Brahic, Pr. Aaron Gitler, Stanford University, U.S.A
  • Pr. Patrik Brundin, Van Andel Institute, U.S.A
  • Pr. Edward Campbell, Loyola University, U.S.A
  • Dr. Francesca Cicchetti, Laval University, Québec, Canada
  • Dr. Laurent Devel, CEA, Saclay, France
  • Pr. Kelly Del Tredici, Ulm University, Germany
  • Dr. Victor Dieriks, Auckland University, New Zealand
  • Pr. Omar El Agnaf, Hamad Bin Khalifa University, Qatar
  • Pr. Ron Kopito, Stanford University, U.S.A
  • Pr. Harm Kampinga, University of Groningen, Netherlands
  • Pr. Jeffrey Kordower, Rush University, Chicago, U.S.A
  • Pr. Michael Heneka, Bonn University, Germany
  • Pr. Beat Meier, ETH, Zürich, Switzerland
  • Dr. Carmen Nussbaum, Pr. Bernd Bukau, University of Heidelberg, Germany
  • Dr. Laurent Roybon and Pr. Jia Yi Li, Lund University, Sweden
  • Pr. Henning Stahlberg, Bale University, Switzerland
  • Dr. Frederic Taran, CEA, Saclay, France
  • Dr. George Tofaris, Oxford University, United Kingdom
  • Dr. Antoine Triller, ENS, Paris, France

Scientific publications

For a complete list of publications, click here.

Selection of publications :

Atomic Force Microscopy Imaging and Nanomechanical Properties of Six Tau Isoform Assemblies. Makky A, Bousset L, Madiona K, Melki R. Biophys J. 2020 Nov 18:S0006-3495(20)30893-6. 

The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodiesVan der Perren A, Gelders G, Fenyi A, Bousset L, Brito F, Peelaerts W, Van den Haute C, Gentleman S, Melki R, Baekelandt V. Acta Neuropathol. 2020 Jun;139(6):977-1000. 

Differential Membrane Binding and Seeding of Distinct α-Synuclein Fibrillar Polymorphs. Shrivastava AN, Bousset L, Renner M, Redeker V, Savistchenko J, Triller A, Melki R. Biophys J. 2020 Mar 24;118(6):1301-1320.

α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb. Rey NL, Bousset L, George S, Madaj Z, Meyerdirk L, Schulz E, Steiner JA, Melki R, Brundin P.Acta Neuropathol Commun. 2019 Dec 30;7(1):221. 

Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy. Guerrero-Ferreira R, Taylor NM, Arteni AA, Kumari P, Mona D, Ringler P, Britschgi M, Lauer ME, Makky A, Verasdonck J, Riek R, Melki R, Meier BH, Böckmann A, Bousset L, Stahlberg H.Elife. 2019.


Find the latest news from the team on the Institute's website

Molecular “fingerprints’ to better identify synucleinopathies
Synucleinopathies : the shape of diseases
Alzheimer’s and Parkinson’s diseases: infectious proteinopathies capture the attention of academicians, 2020
Parkinson’s disease: journey to the Center of alpha-synuclein

Former members of the team

  • Maya Bendifallah (PhD Student)
  • Laurent Brasseur (PhD Student)
  • Jonathan Bonnefoy (PhD Student)
  • Chafika Boudiaf (PhD Student)
  • Luc Bousset (Researcher CNRS)
  • Clémence Brewee (Engineer)
  • Emilie Caroux (PhD Student)
  • Audrey Coens (Engineer)
  • Cyril Dian (Invited researcher)
  • Nicolas Fay (PhD Student)
  • Caroline Héricourt (Engineer)
  • Mehdi Kabani (Researcher CNRS)
  • Joanna Krzewska (Post-Doctoral fellow)
  • Pauline Lagouge-Rousset (Engineer)
  • Céline Martineau (PhD Student)
  • Elodie Monsellier (Researcher CNRS)
  • Yannick Sourigues (Engineer)
  • Samantha Pemberton (PhD Student)
  • Claire Perruchini (Post-Doctoral fellow)
  • Laura Pieri (Post-Doctoral fellow)
  • Gemma Ruiz-Arlandis (PhD Student)
  • Jimmy Savistchenko (PhD Student and Post-Doctoral fellow)
  • Amulya Shrivastava (Post-Doctoral fellow)
  • Stéphane Tchankouo (Post-Doctoral fellow)
  • Kai Wang (PhD Student)