Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.
ER stress
UPR
XBP1s
aging brain
proteostasis
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
17 11 2022
17 11 2022
Historique:
revised:
09
09
2022
received:
22
06
2022
accepted:
16
09
2022
pubmed:
1
11
2022
medline:
22
11
2022
entrez:
31
10
2022
Statut:
ppublish
Résumé
Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.
Identifiants
pubmed: 36314651
doi: 10.15252/embj.2022111952
pmc: PMC9670206
doi:
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
X-Box Binding Protein 1
0
Ern2 protein, mouse
EC 2.7.1.-
Xbp1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e111952Subventions
Organisme : NIA NIH HHS
ID : R01 AG061845
Pays : United States
Organisme : NIA NIH HHS
ID : R35 AG071734
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056259
Pays : United States
Organisme : NIDA NIH HHS
ID : DP1 DA041722
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA048882
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057409
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133552
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS086890
Pays : United States
Informations de copyright
© 2022 The Authors.
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