Glial activation in prion diseases is selectively triggered by neuronal PrPSc.

Abstract

Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrPC selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron-restricted PrPC expression led to copious brain accumulation of PrPSc . As expected, neuron-restricted expression was associated with typical prion disease. However, mice with astrocyte-restricted PrPC expression experienced a normal life span, did not develop clinical disease, and did not show astro- or microgliosis. Besides confirming that PrPSc is innocuous to PrPC -deficient neurons, these results show that astrocyte-born PrPSc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion-infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction.

• Authors: Asvin K K Lakkaraju, Silvia Sorce, Assunta Senatore, Mario Nuvolone, Jingjing Guo, Petra Schwarz, Rita Moos, Pawel Pelczar, Adriano Aguzzi
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 32 Issue 5 Pg. e13056 (09 2022) ISSN: 1750-3639 [Electronic] Switzerland
• PMID: 35178783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Chemical References

• Prions

Topics

• Animals
• Astrocytes (metabolism)
• Mice
• Neuroglia (metabolism)
• Neurons (metabolism)
• Prion Diseases (metabolism)
• Prions (metabolism)