Nouveaux aspects de la biologie de la protéine prion

New insights into the biology of the prion protein

Institut de Génétique Humaine, Cnrs UPR 1142, 141, rue de la Cardonille, 34396 Montpellier Cedex 5, France

^* Sylvain.Lehmann@igh.cnrs.fr

Résumé

La protéine prion joue un rôle majeur dans le déclenchement et la transmission des encéphalopathies spongiformes subaiguës transmissibles. Au cours de la maladie, cette protéine adopte une conformation différente lui conférant des propriétés biochimiques nouvelles. En dépit d’avancées significatives, il existe encore de nombreuses incertitudes concernant la fonction normale de la protéine prion et les mécanismes impliqués dans la neurodégénérescence liée à la maladie. Cet article détaille les récents développements de la biologie de la protéine prion tels que la description de nouvelles formes topologiques de la molécule, sa localisation dans des compartiments cellulaires multiples et ses interactions potentielles avec des partenaires. Toutes ces données semblent essentielles pour la compréhension des fonctions physiologiques et pathologiques de la protéine.

Abstract

Transmissible spongiform encephalopathies form a group of fatal neurodegenerative disorders represented principally by Creutzfeldt-Jakob disease in humans, and by scrapie and bovine spongiform encephalopathy in animals. Also called prion diseases, these disorders are infectious, sporadic, or genetic in origin. Although the nature of the responsible agent of these diseases is uncertain, it is clear that a protein called PrP^Sc plays a central role in their pathology. PrP^Sc is a conformationavariant of a normal protein called PrP^C. PrP^C is a glyco-protein expressed by most tissues and is attached on the cell membrane through a glycosyl-phosphatidylinosito anchor, which is consistent with roles in cell adhesion, igand uptake, or transmembrane signaling. NMR studies revealed that the protein has a globular domain and a long amino-terminal tail that contains repeated octa-peptide domains, which bind metal ions with high affini-ties. PrP^C is localized on the cell membrane in detergent resistant microdomains and may be part of functiona complexes with other molecules such as N-CAM, Laminin or kinases. This is particularly relevant in view of the possible role of the molecule in signal transduction, resistance to oxidative stress and neuronal survival. The description both in vitro and in vivo, of a transmembrane form of PrP that can accumulate in the endoplas-mic reticulum has attracted a lot of attention. The role of such isoforms in neurodegeneration, as well as the presence of PrP into the cytoplasm and in the nucleus where it may interact with nucleic acids are still deba-ted. In conclusion, it appeared that the understanding of the PrP biology is essential to the understanding of the physiological function of this protein as well as for its pathological conversion since its trafficking governs the generation of PrP^Sc.