Prion diseases: modelling the process of dissemination and neuroinvasion

Background and challenges

In the prion paradigm framework, host-encoded monomeric proteins are converted into misfolded aggregated assemblies, which serve as a template for further autocatalytic recruitment and conversion in the brain. Since the late 2000s, the prion paradigm has been extended to other neurodegenerative diseases due to protein misfolding such as Alzheimer's and Parkinson's disease.

In mammalian prion diseases, also known as Transmissible Spongiform Encephalopathies (TSE), prion assemblies (PrP^Sc), formed from the cellular prion protein (PrP^C), contain all the structural information necessary to their replication and their specific stereotyped disease phenotype in the infected host. In TSE, multiple PrP^Sc conformational variants exist. They define the prion strains and dictate specific physiopathological patterns such as region-specific PrP^Sc deposits in the same host species. Although self-replicative processes provide a mechanistic framework for the prion paradigm, to date there is no mechanistic link between prion replication, the neuroinvasion process and the strain-specific neuropathological pattern

Goals

The PrionDif project seeks to develop a multi-scale mechanistic model accounting for the spatiotemporal dynamic of prion spreading within the brain by integrating experimental observations with an effective model of prion replication which takes into account the dynamicity of PrP^Sc assemblies. By integrating the spatio-temporal mapping of the spread of prion replicative centres with the prion replication/dissemination model, we aim to build a synthetic multi-scale model of prion structural diversification and lesional propagation. This open-access model will allow us to investigate which parameters of the prion replication process specific to each strain dictate the progression of the disease and the apparition of strain specific PrP^Sc deposition patterns.

Ultimately, this synthetic approach will allow the identification of key processes to enable therapeutic advances and promote early diagnosis

Contact - coordination :

Partnerships

INRAE participants

Partners

Journal article

• A. Igel, B. Fornara, H. Rezaei and V. Béringue (2023). "Prion assemblies: structural heterogeneity, mechanisms of formation, and role in species barrier." Cell Tissue Res 392(1): 149-166 
• Fornara, B., Igel, A., Béringue, V., Martin, D., Sibille, P., Pujo-Menjouet, L., Rezaei, H., The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics, ISCIENCE (2024), doi: https://doi.org/10.1016/j.isci.2024.111381. 
• Bohl, J., Moudjou, M., Herzog, L., Reine, F., Sailer, F., Klute, H., Halgand, F., Rest, G. V., Boulard,Y., Beringue, V., Igel, A. & Rezaei, H. (2023). The Smallest Infectious Substructure Encoding the Prion Strain Structural Determinant Revealed by Spontaneous Dissociation of Misfolded Prion Protein Assemblies. J Mol Biol. 435, 168280. https://doi.org/10.1016/j.jmb.2023.16828 
• B. Fornara, A. Igel, L. Pujo-Menjouet, V. Béringue, H. Rezaei (in preparation). Modeling prion assemblies’coevolution and spreading through neuron-network. Submission in Plos Computational Biology 

Conference papers

• 6th International Symposium on Pathomechanisms of Amyloid Diseases (Tallahassee, Florida,
  USA), December 2024. Dynamic of prion assemblies in relation with tissue spreading and strain
  mutation
• ICNAAM (Heraklion, Greece), September 2024. Prion tissue spreading and strain evolution
• INPEC (Taipe, Taiwan), May 2024. Dynamic of prion assemblies and the consequences of the
  coexistence of multiple prion conformations. 
• Neurophysiology workshop (Conception-Chili), January 2024: Prion Pathologies 
• 5th International symposium on Pathomechanisms of Amyloid Diseases (Bordeaux, France),
  September 2023. Dynamic of prion assemblies during replication and dissemination. 
• Belgium Biophysical society (Liege, Belgium), September 2023. Complexity and selforganization
  of prion assemblies during prion replication 
• Molecular Bases of Proteinopathies (Michigan-USA, webinar), February 2023: The consequences
  of the coexistence of multiple prion conformations on the dynamic of prion and tissue invasion. 
• Neurophysiology workshop (Conception-Chili), January 2023: Prion Pathologies
• Protein quality control workshop (Conception-Chili), January 2023: Light scattering methods
  for the characterization of protein assemblies’ quaternary structure.
•  Mathematical Methods for the Study of Self-organization in the Biological Sciences (Austria,
  Wien), November 2022: The consequences of the coexistence of multiple prion conformations
  on the dynamic of prion assemblies and tissue invasion.
• Prion 2022. (Göttingen, Germany). September 2022: The smallest prion substructure encoding
  the strain structural determinant revealed by spontaneous dissociation of prion assemblies
• CECAM workshop, France (Paris, IBPC), Jun 2022: Dynamics of prion assemblies and the
  coexistence of multiple prion conformations. 
• Vibrational Spectroscopy Society (Belgium, Nivet) May 2022: Prion assemblies at single
  molecule level
• Cellular and Protein Homeostasis workshop (Switzerland, Lausanne), February 2022: Dynamic
  of prion assemblies governed by catalytical exchange between multiple prion conformation