Abstract
The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases.
Highlights
The transition from the cellular prion protein (PrPC) to its misfolded, amyloidogenic conformer (PrPSc), is crucial to the generation of infectious prions [1], and is the central feature of a class of invariably fatal, transmissible neurodegenerative disorders termed prion diseases [2]
We analysed different time points during prion disease and different combinations of both mouse and prion strains [25,26]. We found that these transcripts are either unchanged (Nlrp3 and Il1b) or only moderately upregulated (Pycard and, to a less extent, Casp1) in the latest stages of prion disease with respect to baseline levels (S1B Fig.)
We have investigated the role of the NLRP3 inflammasome on prion disease in vivo
Summary
The transition from the cellular prion protein (PrPC) to its misfolded, amyloidogenic conformer (PrPSc), is crucial to the generation of infectious prions [1], and is the central feature of a class of invariably fatal, transmissible neurodegenerative disorders termed prion diseases [2]. In the central nervous system (CNS), prion diseases are accompanied by microglia activation [5,6,7]. This activation may have beneficial effects, since microglial engulfment of cerebral apoptotic bodies is an important mechanism of prion clearance [8]. There is little understanding of the role of the innate immune system against prions [9], and in particular of the mechanisms by which prions activate microglial cells
Sign-in/Register to view highlights & summary 
Published Version (
Free)
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.
