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

Heather L Smith,Oliver J Freeman,Adrian J Butcher,Staffan Holmqvist,Ibrahim Humoud,Tobias Schätzl,Daniel T Hughes,Nicholas C Verity,Dean P Swinden,Joseph Hayes,Lis De Weerd,David H Rowitch,Robin J.M Franklin,Giovanna R Mallucci

doi:10.1016/j.neuron.2019.12.014

Heather L Smith, Oliver J Freeman + Show 12 more

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https://doi.org/10.1016/j.neuron.2019.12.014

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SummaryRecent 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.

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The buildup of misfolded proteins, characteristic of many neurodegenerative diseases, is a cellular stress that results in activation of the unfolded protein response (UPR), a signaling cascade that aims to restore protein homeostasis (Ron and Walter, 2007)
We show that chronic protein kinase R-like ER kinase (PERK)-eIF2a signaling in astrocytes drives a distinct pathogenic reactivity state both in vitro and in vivo
Astrocytic PERK-eIF2a Signaling Drives a UPRReactivity State In Vivo that Is Reversed by Genetic Modulation of the Pathway Given the effect of PERK signaling on astrocyte reactivity in vitro (Figures 1E and S1H), we examined whether this occurs in vivo

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The buildup of misfolded proteins, characteristic of many neurodegenerative diseases, is a cellular stress that results in activation of the unfolded protein response (UPR), a signaling cascade that aims to restore protein homeostasis (Ron and Walter, 2007). In several mouse models of neurodegeneration, chronic PERK-eIF2a-P signaling results in the sustained reduction in global protein synthesis rates, leading to synaptic failure and neuronal loss (Moreno et al, 2012; Radford et al, 2015). We show that chronic PERK-eIF2a signaling in astrocytes drives a distinct pathogenic reactivity state both in vitro and in vivo. This state, which we term ‘‘UPR’’ reactive, is characterized by an astrocytic secretome devoid of synaptogenic properties. The pathogenic role of PERK over-activation has a significant, non-cell-autonomous component, generating a distinct reactivity state in astrocytes principally through loss of synaptotrophic function; this provides multiple new targets for Neuron 105, 855–866, March 4, 2020 a 2019 The Authors.

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