From Prion diseases to neurodegenerative disorders: Is transcellular spread of misfolded proteins a shared mechanism of neurodegeneration?

The misfolding and progressive aggregation of disease-linked proteins in the nervous system, together with spatiotemporal spreading of pathological lesions through the brain is a feature of many neurodegenerative diseases. Examples of such Protein Misfolding Diseases (PMDs) include Alzheimer disease (characterized by the accumulation of the beta-amyloid peptide (Ab) and hyperphosphorylated tau), Parkinson disease (with aggregates of a-synuclein), Huntington’s disease (in which aggregates of mutant huntingtin are formed), ALS and Frontotemporal dementia (in which deposits of TAR DNA-binding protein (TDP)-43 occur). The above mentioned hallmarks are very reminiscent of Transmissible spongiform encephalopathies (TSEs), which are rare infectious neurodegenerative diseases associated with abnormal folding, progressive aggregation of toxic prion protein (PrP srapie or PrP^SC) and spatiotemporal spreading of pathological lesions. The discovery-a few decades ago- of the « proteinaceous nature of infectious particles » as being responsible for TSE, gave rise to the Prion hypothesis. The central tenet of this hypothesis states that the misfolded PrP^SC recruits healthy PrP (PrP cellular) and imposes its abnormal conformation onto it thereby converting it into a toxic specie.  The toxic PrP^SC can spread from cell to cell, propagating the pathological self-templating process. Following the release of this concept, it was suggested that the progressive accumulation of protein aggregates in other PMDs might form in a manner analogous to that of misfolded PrP in TSEs. The progressive spread of pathological lesions from region to region in patterns that match neuronal connectivity strengthened the concept of « Pathological Protein Propagation », a phenomenon in which pathogenic proteins might trigger a « prion-like templating » mechanism and spread in a toxic cascade following anatomical pathways.

                A meeting on the role of pathological protein propagation in neurodegenerative diseases will take place on the 11^th of March 2019, in Basel, Switzerland. This event will bring together international experts who will discuss the most recent data on pathological protein propagation in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis.

Finally, the involvement of this phenomenon in neurodegenerative diseases will be discussed during a round table. During this round table/controversy debate, the strengths and weaknesses of the concept will be raised, both from a research and therapeutic perspective.

9h00       9h30       Welcome coffee

9h30       9h45       Introduction :  Eline Pecho-Vrieseling (Basel, Switzerland)

9h45             Session 1. Chaired by Paolo Paganetti (Torricella-Taverne, Switzerland)

9h45       10h15    A. Aguzzi (Zürich, Switzerland)

                             Introduction: The concept of Pathological Protein Propagation: an historical overview

10h15    10h45    R. Melki (Gif sur Yvette, France)

                            Prion-like propagation of alpha-synuclein assemblies and the molecular basis of distinct synucleinopathies

10h45-11h15       Coffee break

11h15    11h45    C. Brou (Paris, France)

                             Role of Tunnelling nanotubes in the spreading of amyloid proteins in neurodegenerative diseases

11h45    12h15    M. Polymenidou (Zürich, Switzerland)

                             The many faces of TDP-43 aggregation

12h15    14h00    Lunch break

14h00          Session 2. Chaired by Efthalia Natalia Tousiaki (Basel, Switzerland)

14h00    14h30    M. Meyer-Luehmann (Freiburg, Germany)

                            The effect of Abeta seeding on different cell types

14h30    15h00    Eline Pecho-Vrieseling (Basel, Switzerland)

                             Exploring the link between neuronal connectivity, misfolded mutant huntingtin spreading and non-cell autonomous pathology

15h00    15h30    Coffee break

15h30    17h00    Round table-controversy debate (all speakers)

                            Is pathological protein propagation involved in the aetiology of neurodegenerative disorders?

Moderated by Paolo Paganetti

Basel, 11th of March 2019.

Venue: Museum Kleines Klingental,

Unterer Rheinweg 26

Deadline for Registration : March 1st, 2019

Neurex workshops are part of the cycle B5 of the University of Basel. They allow students to gain Credit Points from attending workshops/meetings.

This specific workshop will give rise to the attribution of 1/2 CP.

Important: Full rules & how to proceed available here.