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

Neuron. 2020 Mar 4;105(5):855-866.e5. doi: 10.1016/j.neuron.2019.12.014. Epub 2020 Jan 7.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Endoplasmic Reticulum Stress / drug effects
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Initiation Factor-2B / metabolism*
  • In Vitro Techniques
  • Memory
  • Mice
  • Neurodegenerative Diseases / metabolism*
  • Phosphorylation
  • Prion Diseases / metabolism*
  • Protein Biosynthesis
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism
  • Signal Transduction
  • Synapses / metabolism*
  • Thapsigargin / pharmacology
  • Transcriptome
  • Tunicamycin / pharmacology
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / physiology*
  • eIF-2 Kinase / metabolism*

Substances

  • Enzyme Inhibitors
  • Eukaryotic Initiation Factor-2B
  • Tunicamycin
  • Thapsigargin
  • PERK kinase
  • eIF-2 Kinase
  • Ppp1r15a protein, mouse
  • Protein Phosphatase 1