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Prion pathogenesis in the absence of NLRP3/ASC inflammasomes

Mario Nuvolone1, Silvia Sorce1, Petra Schwarz1

  • 1Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.

Plos One
|February 12, 2015
PubMed

Insights

The NLRP3 inflammasome is not essential for prion disease progression or pathology in mice. Genetic deletion of NLRP3 or ASC did not alter scrapie incubation times or IL-1β levels, challenging therapeutic targeting.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Prion diseases involve the accumulation of misfolded prion proteins (PrPSc) and microglia activation in the central nervous system.
  • The NLRP3 inflammasome, crucial for IL-1β release, was previously implicated in prion-related inflammation in vitro.
  • Its role in prion disease pathogenesis in vivo remained uninvestigated.

Purpose of the Study:

  • To investigate the role of the NLRP3 inflammasome and its adaptor ASC in prion disease pathogenesis using a mouse model.
  • To determine if NLRP3 inflammasome components are essential for disease progression and neuroinflammation.

Main Methods:

  • Intracerebral inoculation of scrapie prions (strain RML) into wild-type, Nlrp3-/-, and Pycard-/- mice.
  • Monitoring of scrapie attack rates and incubation times.
  • Histological and biochemical analysis of brain tissue, including IL-1β quantification.

Main Results:

  • Mice lacking NLRP3 or ASC exhibited similar scrapie susceptibility and incubation periods compared to wild-type controls.
  • Genetic ablation of NLRP3 or ASC did not significantly affect the classic features of prion disease.
  • Brain IL-1β levels at the terminal stage of disease were not significantly impacted by the absence of NLRP3 or ASC.

Conclusions:

  • The NLRP3 inflammasome and ASC are not critical for prion disease pathogenesis in this mouse model.
  • These findings suggest that NLRP3 and ASC are unlikely to be effective therapeutic targets for prion diseases.
  • The study refutes the claimed in vitro findings regarding the essential role of NLRP3 in prion disease.

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