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Séminaire impromptu - Yann FichouFrom solution tau to amyloid aggregates: pathway matters a great deal

Abstract :

The seminar will take place the 3rd of May 2018, at 2pm in the IECB amphitheatre, 2 rue Robert Escarpit Pessac. Contact: Antoine Loquet, a.loquet@iecb.u-bordeaux.fr


 The intrinsically disordered tau protein is known to aggregate into amyloid filaments involved in many neurodegenerative diseases,
including Alzheimer’s disease (AD) and Frontotemporal dementia (FTD). Different types of aggregates, called strains, are thought to be involved in distinct pathologies and to faithfully propagate by converting naïve monomers, recalling a prion-like behavior. Yet, there is no structural basis for this seed-assisted conversion and for the selection of well-define strain. In this presentation, I will provide new insights into tau aggregation pathways by using complementary biophysical methods, including electron paramagnetic resonance spectroscopy (EPR).

Most of the studies aiming at understanding tau aggregation mechanisms and driving forces have been carried out using heparin to trigger recombinant tau aggregation. This protocol was thought to create a model aggregate for AD filaments.

I will show that polyanions, such as heparin or RNA, act as a brace that converts functional tau into aggregation-prone conformers. We argue that disease mutations, such P301L, shift the conformational ensemble toward pathological conformers, thereby facilitating the initial conformational rearrangement that triggers the aggregation cascade. However, because polyanions are unstructured polymers, they provide a poor scaffold for filament formation, resulting in imperfectly packed amyloid aggregates. This mispacking has strong consequences on the properties of the mature fibers. We show that upon removal of the cofactors (Heparin or RNA), tau monomers spontaneously disassemble from mature fibers and lose their aggregation-prone conformation.

In addition, I will show that heparin-induced filaments are drastically different from brain-extracted AD filaments. On the one hand, the main structural features of AD filaments are not reproduced by heparin aggregates. On the other hand, even when embedded in amyloid fibers, the tau protein exists in heterogeneous conformations, showing that heparin is incapable of selecting a pathway toward a given strain. We suggest this is the main reason why heparin-induced filaments have poor seeding capacity.

We argue that the quality of amyloid aggregates, i.e. the packing and conformations of the monomeric subunits, is a predominant factor that control their properties and therefore their biological relevance.

  (a.loquet @ iecb.u-bordeaux.fr)

Selected publications

Conformation-based assay of tau protein aggregation
Y. Fichou, N.A. Eschmann, T.J. Keller, S. Han, Methods Cell Biol., 141 (2017) 89-112.

Scientific focus :

Yann's research focuses on protein aggregation which is involved in many diseases, such as Alzheimer's Disease, Parkinson's Disease, and others. His aim is to understand why proteins aggregate and to explain how the complex process of aggregation takes place. Yann is particularly interested in the earliest stages of aggregation.