title: Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases.
abstract: BACKGROUND
  The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases
  
  
  RESULTS
  Here, we show that PrP can interact in vitro with acetylcholinesterase (AChE), a key protein of the cholinergic system in neural and non-neural tissues. This heterologous association induced aggregation of monomeric PrP and modified the structural properties of PrP amyloid fibrils. Following its recruitment into PrP fibrils, AChE loses its enzymatic activity and enhances PrP-mediated cytotoxicity. Using several truncated PrP variants and specific tight-binding AChE inhibitors (AChEis), we then demonstrate that the PrP-AChE interaction requires two mutually exclusive sub-sites in PrP N-terminal domain and an aromatic-rich region at the entrance of AChE active center gorge. We show that AChEis that target this site impair PrP-AChE complex formation and also limit the accumulation of pathological prion protein (PrPSc) in prion-infected cell cultures. Furthermore, reduction of AChE levels in prion-infected heterozygous AChE knock-out mice leads to slightly but significantly prolonged incubation time. Finally, we found that AChE levels were altered in prion-infected cells and tissues, suggesting that AChE might be directly associated with abnormal PrP.
  
  
  CONCLUSIONS
  Our results indicate that AChE deserves consideration as a new actor in expanding pathologically relevant PrP morphotypes and as a therapeutic target.
authors: Joan
authors: J
authors: Torrent
authors: Alba
authors: A
authors: Vilchez-Acosta
authors: Diego
authors: D
authors: Muñoz-Torrero
authors: Marie
authors: M
authors: Trovaslet
authors: Florian
authors: F
authors: Nachon
authors: Arnaud
authors: A
authors: Chatonnet
authors: Katarina
authors: K
authors: Grznarova
authors: Isabelle
authors: I
authors: Acquatella-Tran Van Ba
authors: Ronan
authors: R
authors: Le Goffic
authors: Laetitia
authors: L
authors: Herzog
authors: Vincent
authors: V
authors: Béringue
authors: Human
authors: H
authors: Rezaei
mesh_terms: D000110:Acetylcholinesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D000682:Amyloid; D018620:PrPSc Proteins; D011328:Prions; D000110:Acetylcholinesterase