Sylvie NOINVILLE
CNRS-Sorbonne Universités (UPMC), Laboratoire MONARIS, Paris 75005
Vendredi 29 juin à 14h (salle Magat) :
“Membrane and surface interaction of Prion protein assemblies : insights into the mechanism of neurotoxicity”
Résumé
In the case of Prion protein (PrP), the α-to-β conversion of normal PrPC to its pathological isoform PrPSc is a key event in transmissible encephalopathies. A convergence of evidence strongly suggests that soluble oligomers or small fibrillar fragments of PrP, as on- or off-pathway products, are considered to be the most toxic species in Prion diseases. Surface-induced conformational changes of PrP are at the origin of accelerating fibrillation or to prevent it depending on the chemical nature of solid synthetic models or lipid bilayers, as shown by FTIR-ATR [1]. On- or off-pathway oligomers were obtained depending on the single mutation or truncation of the full length primary sequence up to a minimal region, and then purified. The impairments of the membrane by the soluble oligomers are correlated to their neuronal toxicities at submicromolar concentrations as shown by cell culture assays [2]. Deciphering the complex network of lipid interactions and conformational diversity of the PrP protein leading to soluble oligomers of controlled size will help for understanding by which mechanism amyloidogenic proteins mediate neurotoxicity.
References
1. Chich, J. F. ; Chapuis, C. ; Henry, C. ; Vidic, J. ; Rezaei, H. ; Noinville, S., Vesicle permeabilization by purified soluble oligomers of prion protein : a comparative study of the interaction of oligomers and monomers with lipid membranes. J Mol Biol 2010, 397, (4), 1017-30.
2. Crosnier, S. ; Beringue, V. ; Rezaei, H. ; Noinville, S., Membrane permeabilization and neuronal toxicities induced by PrP oligomers : essential role of the H2H3 oligomerization domain for neurotoxicity J.Biol.Chem submitted.
