Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration.
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
Signal Transduction
Synapses
/ metabolism
Thapsigargin
/ pharmacology
Transcriptome
Tunicamycin
/ pharmacology
Unfolded Protein Response
/ drug effects
eIF-2 Kinase
/ metabolism
LCN2
PERK signalling
astrocyte reactivity state
astrocytes
neurodegeneration
neuroprotection
secretome
synapse
translational neuroscience
unfolded protein response
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
04 03 2020
04 03 2020
Historique:
received:
26
07
2019
revised:
06
11
2019
accepted:
09
12
2019
pubmed:
12
1
2020
medline:
8
7
2020
entrez:
12
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31924446
pii: S0896-6273(19)31056-6
doi: 10.1016/j.neuron.2019.12.014
pmc: PMC7054837
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Eukaryotic Initiation Factor-2B
0
Tunicamycin
11089-65-9
Thapsigargin
67526-95-8
PERK kinase
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
Ppp1r15a protein, mouse
EC 3.1.3.16
Protein Phosphatase 1
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
855-866.e5Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0701476
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M010503/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R024820/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802545
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S00503X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300338
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700392
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K008803/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 201487/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300336
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U132692719
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests. O.J.F. is now an employee of AstraZeneca.
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