Neuron
Volume 105, Issue 5, 4 March 2020, Pages 855-866.e5
Journal home page for Neuron

Article
Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration

https://doi.org/10.1016/j.neuron.2019.12.014Get rights and content
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Highlights

  • PERK-eIF2α signaling in astrocytes generates a distinct “UPR”-reactivity state

  • UPR-reactive astrocytes have an altered secretome, with reduced synaptogenic factors

  • UPR-reactive astrocytes fail to support synaptogenesis in vitro

  • Targeting the astrocytic UPR prevents synapse and neuronal loss in prion-diseased mice

Summary

Recent interest in astrocyte activation states has raised the fundamental question of how these cells, normally essential for synapse and neuronal maintenance, become pathogenic. Here, we show that activation of the unfolded protein response (UPR), specifically phosphorylated protein kinase R-like endoplasmic reticulum (ER) kinase (PERK-P) signaling—a pathway that is widely dysregulated in neurodegenerative diseases—generates a distinct reactivity state in astrocytes that alters the astrocytic secretome, leading to loss of synaptogenic function in vitro. Further, we establish that the same PERK-P-dependent astrocyte reactivity state is harmful to neurons in vivo in mice with prion neurodegeneration. Critically, targeting this signaling exclusively in astrocytes during prion disease is alone sufficient to prevent neuronal loss and significantly prolongs survival. Thus, the astrocyte reactivity state resulting from UPR over-activation is a distinct pathogenic mechanism that can by itself be effectively targeted for neuroprotection.

Keywords

astrocytes
astrocyte reactivity state
neurodegeneration
synapse
secretome
neuroprotection
unfolded protein response
PERK signalling
LCN2
translational neuroscience

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