Abstract
IntroductionThe prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseasesResultsHere, 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.ConclusionOur results indicate that AChE deserves consideration as a new actor in expanding pathologically relevant PrP morphotypes and as a therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0188-0) contains supplementary material, which is available to authorized users.
Highlights
The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases
The potent tight-binding AChE inhibitors (AChEis) huprine Y and Hup8TH limit Misfolded pathological PrP conformer (PrPSc) accumulation in prion-infected cell cultures First we asked whether AChE actively participates in PrPSc accumulation
Western blot analysis after Proteinase K (PK) digestion of crude extracts from confluent, prion-infected MovS6 cells cultured in the presence of 20 μM of each AChEi or vehicle alone for 6 days showed that only huprine Y inhibited PrPSc accumulation (Figure 1a)
Summary
The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases. The prion protein (PrP) plays a key role in the pathogenesis of transmissible spongiform encephalopathies, known as prion diseases [1,2]. These fatal and infectious neurodegenerative conditions are caused by prions, which consist mainly, if not exclusively, of misfolded pathological conformers (PrPSc) of the host cellular PrP isoform (PrPC) [3]. While the massive contribution of PrP conformational changes to the etiology of prion diseases is widely recognized, less is known about the role of other molecules that interact directly with PrP. We found that AChE levels were altered in brain and spleen of prion-infected mice and in infected cell cultures compared to non-infected controls
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
