Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration.
Neuron
; 105(5): 855-866.e5, 2020 03 04.
Article
in En
| MEDLINE
| ID: mdl-31924446
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Synapses
/
Astrocytes
/
Prion Diseases
/
Neurodegenerative Diseases
/
EIF-2 Kinase
/
Eukaryotic Initiation Factor-2B
/
Unfolded Protein Response
Type of study:
Etiology_studies
Limits:
Animals
Language:
En
Journal:
Neuron
Journal subject:
NEUROLOGIA
Year:
2020
Document type:
Article
Affiliation country:
Reino Unido