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Protein misfolding and aggregation in neurodegenerative diseases


Team leader : Ronald MELKI (Research director CNRS)


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 Ronald MELKI


Published on 31 January 2024

Team

Research topics

Methods & expertise

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Publications


The team TOP

The team “Misfolding and Aggregation of Proteins in Neurodegenerative Diseases” counts eight members and occupies a key position in a network of national and international collaborations structured around and through several European contracts.
The team focusses on the structure-pathology relationship in various incurable neurodegenerative diseases.





  • Chloé BAROIN (PhD student CEA, 2023-2026), codirected Anselme Perrier
  • Annabelle BONINO (PhD student CEA, 2020-2023), codirected par Laurent Devel
  • Dory COHEN (Engineer, 2024-2025)
  • Milena GIROMINI (PhD student CEA, 2022-2025)
  • Tristan HERSKOVITS-SERRE (Engineer, 2024-2025)
  • Ronald MELKI (Research director, CNRS)
  • Bradel NGONZA-NITO (PhD student CNRS, 2023-2026)
  • Gaëtan OSSARD (PhD student CEA, 2022-2025), codirected by Eugénie Roméro-Laboureur​
  • Virginie REDEKER (Researcher, INSERM) 
  • Nolwen REY (Researcher, CNRS)
  • Camille THIBERGE (Post-doctoral fellow CEA, 2024-2025)




Research topics RES

Neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's diseases are characterized by the accumulation of proteins in an aggregated form in the nervous system
These proteinopathies result from the misfolding and aggregation of distinct proteins. These aggregated proteins are able to propagate and multiply in the brain, causing progressive and irreversible degeneration of neuronal cells. 
We have demonstrated that each of the proteins implicated in the neurodegenerative diseases listed above forms aggregates, which differ in their structures and are named “polymorphs”. These polymorphs are able to differentially target distinct neuronal populations and induce the aggregation of ‘healthy’ proteins while maintaining their physical and pathological characteristics. These polymorphs therefore constitute strains, which, due to their distinct characteristics, could contribute to the clinical heterogeneity observed in different neurodegenerative diseases due to the aggregation of the same protein.

Our work aims to:

  • Dissecting the molecular events leading to protein aggregation and to the spread of pathological protein strains from cell to cell
  • Characterizing the structure of the different strains produced in vitro and derived from patients, and elucidating their pathogenic properties
  • Developing approaches to prevent or reduce the aggregation and the spreading of different strains




Methods and expertise EXP




Current fundings 

  1. Agence Nationale de la Recherche : Development of synuclein model in Macaque, SUMMA
  2. Agence Nationale de la Recherche, ANR JC-JC : Untangling the selectivity of alpha-synuclein pathology transmission in synucleinopathies: role of intra and extracellular environments, SYNSELECT 
  3. Fondation pour la Recherche Médicale :  Nouveaux mécanismes physiopathologiques impliqués dans la maladie d'Alzheimer: vers de nouvelles approches thérapeutiques
  4. France Parkinson : Bases moléculaires de la propagation sélective des agrégats de l’alpha-synucléine dans le système nerveux central dans la maladie de Parkinson 
  5. European Flag ERA-NET :  Translational platform for MSA : Elucidation of disease mechanisms and drug discovery TrapMEDD
  6. European ERA-Per-Medd : Prodromal determinants for phenoconversion of idiopathic RBD to alpha-synucleinopathies (PD, DLB, MSA) DEEPEN-iRBD 
  7. Fondation de France : Selective interactors of alpha-synuclein fibrils derived from Parkinson patients: Identification and functional assessment using human iPS-derived neurons
  8. European Commission, Innovative Medicines Initiative : Identification of druggable targets modulating misfolded proteins in Alzheimer  ’s and Parkinson’s diseases, IMPRIND www.imprind.org
  9. European Commission, Innovative Medicines Initiative : A quantitative approach towards the characterisation of mitochondrial dysfunction in Parkinson’s Disease, PD-MitoQUANT www.pdmitoquant.eu
  10. Mutuelles AXA - Mécénat Santé : Les partenaires des dépôts de protéines tau pathogéniques dans la maladie d’Alzheimer : identification, fonction et nouvelles pistes diagnostiques et thérapeutiques




Scientific awards

  • Coups d'Elan pour la Recherche Française 2011, Bettencourt Sc​hueller 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

Principal active external collaborations COLL

  • Pr. Adriano Aguzzi, Université de Zurich, Suisse
  • Pr. Veerle Baekelandt, Université de Louvain, Belgique
  • Pr. Aaron Gitler et Pr Jin Hyung Lee, Université de Stanford, Etats-Unis
  • Pr Bernd Bukau, Université de Heidelberg, Allemagne
  • Pr. Edward Campbell, Université Loyola, Etats-Unis
  • Dr. Francesca Cicchetti, Université Laval, Québec, Canada
  • Dr. Yaroslau Compta, CLINIC, Barcelone, Espagne
  • Dr. Laurent Devel, CEA, Saclay, France
  • Pr. Kelly Del Tredici et Heiko Braak, Université de Ulm, Allemagne
  • Dr. Victor Dieriks, Université de Auckland, Nouvelle-Zélande
  • Pr. Omar El Agnaf, Université Hamad Bin Khalifa, Qatar
  • Dr. Zoher Gueroui, ENS, Paris, France
  • Pr. Ron Kopito, Université de Stanford, Etats-Unis
  • Pr Rejko Krüger, Université du Luxembourg, Luxembourg
  • Pr. Harm Kampinga, Université de Groningen, Pays-Bas
  • Dr Brian Killinger, Université Rush, Chicago, Etats-Unis
  • Dr. Janine Kirstein, Université de Breme, Allemagne
  • Pr. Jeffrey Kordower, Université de l’Arizona, Tempe, Etats-Unis
  • Pr. Michael Heneka, Université du Luxembourg, Luxembourg
  • Pr. Hilal Lashuel, EPFL Lausanne, Suisse
  • Dr. Carmen Nussbaum, Université de Munich, Allemagne
  • Pr. Paola Picotti, ETH Zürich, Suisse
  • Pr. Jochen Prehn, RCSI, Dublin, Irlande
  • Pr. Henning Stahlberg, EPFL Lausanne, Suisse
  • Dr. Frederic Taran, CEA, Saclay, France
  • Dr. George Tofaris, Université d’Oxford, Royaume-Uni
  • Dr. François Treussart, Ecole Normale Supérieure Paris Saclay, Saclay, France
  • Dr. Antoine Triller et Dr. Terence Strick, ENS, Paris, France
  • Dr. Miquel Vila, VHIR, Barcelone, Espagne
  • Pr. Leonidas Stefanis et Kostas Vekrellis, Université d’Athènes, Grèce
  • Pr. Mauno Vihinen, Université de Lund, Suède
  • Dr. Friederike Zunke, Université d’Erlangen, Allemagne

Scientific publications PUB

For a complete list of publications, click here.


Selection of publications :


Host oligodendrogliopathy and ɑ-synuclein strains dictate disease severity in multiple system atrophy. Torre-Muruzabal T, Van der Perren A, Coens A, Gelders G, Barber Janer A, Camacho-Garcia S, Klingstedt T, Nilsson P, Stefanova N, Melki R, Baekelandt V, Peelaerts W. Brain 2023 Jan 5;146(1):237-251. 

The differential solvent exposure of N-terminal residues provides « fingerprints » of alpha-synuclein fibrillar polymorphs. Landureau M, Redeker V, Bellande T, Eyquem S, Melki R. J Biol Chem. 2021, 296:100737 [Pubmed ] 

Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons. Tanudjojo B, Shaikh SS, Fenyi A, Bousset L, Agarwal D, Marsh J, Zois C, Heman-Ackah S, Fischer R, Sims D, Melki R, Tofaris GK.  Nat Commun. 2021, 12:3817. [Pubmed ] 

The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Van 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. [Pubmed ] 

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. [Pubmed] 

Clustering of Tau fibrils impairs the synaptic composition of α3-NA+/K+- ATPase and AMPA receptors. Shrivastava AN, Redeker V, Pieri L, Bousset L, Renner M, Madiona K, Mailhes-Hamon C, Coens A, Buée L, Hantraye P, Triller A, Melki R. EMBO J. 2019, 38:e99871. [Pubmed ] 



Press-release


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Alumni

Researchers & invited researchers
Luc Bousset
Cyril Dian
Mehdi Kabani
Elodie Monsellier 

Post-doctoral fellows
Gonzalo de Arriba Zera
Alexis Fenyi
Medeva Ghee
Joanna Krzewska
Elodie Monsellier
Alain Perret
Laura Pieri
Sandra Pucciarelli
Jimmy Savistchenko
Amulya Shrivastava
Stéphane Tchankouo


PhD candidates
Maya Bendifallah
Luc Bousset
Laurent Brasseur
Annabelle Bonino
Jonathan Bonnefoy
Chafika Boudiaf
Emilie Caroux
Nicolas Fay
Alexis Fenyi
Maud Landureau
Céline Martineau
Samantha Pemberton
Jimmy Savistchenko
Carine Thual
Kai Wang


Assistant engineers
Audrey Coens
Ania Alik
Gérard Batelier
Clémence Brewee
Steven Dubois
Fatima El Khadali
Alison Gervais
Caroline Héricourt
Pauline Lagouge-Rousset
Karine Madiona
Yannick Sourigues
Delphine Thibaut

Technicians
Tracy Bellande


Team

Research topics

Methods & expertise

Collaborations

Publications