title: Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders.
abstract: Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrP(res)), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders.
authors.affiliation: AP-HP, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisiére et Universite´ Paris Descartes, Paris, France.
authors.forename: Katell
authors.initials: K
authors.lastname: Peoc'h
authors.forename: Etienne
authors.initials: E
authors.lastname: Levavasseur
authors.forename: Emilien
authors.initials: E
authors.lastname: Delmont
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Isabelle
authors.initials: I
authors.lastname: Laffont-Proust
authors.forename: Nicolas
authors.initials: N
authors.lastname: Privat
authors.forename: Yassmine
authors.initials: Y
authors.lastname: Chebaro
authors.forename: Céline
authors.initials: C
authors.lastname: Chapuis
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedoucha
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brandel
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerriere
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kemeny
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Hauw
authors.forename: Michel
authors.initials: M
authors.lastname: Borg
authors.forename: Human
authors.initials: H
authors.lastname: Rezaei
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.forename: Stéphane
authors.initials: S
authors.lastname: Haïk
mesh_terms: D019943:Amino Acid Substitution; D003001:Cloning, Molecular; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000473:pathology; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D011328:Prions