Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.
Felipe Cabral-MirandaGiovanni TamburiniGabriela MartinezAlvaro O ArdilesDanilo B MedinasYannis GerakisMei-Li Diaz HungRené VidalMatias FuentealbaTim MiedemaClaudia Duran-AniotzJavier DiazCristobal Ibaceta-GonzalezCarleen M SabusapFrancisca Bermedo-GarciaPaula MujicaStuart S AdamsonKaitlyn VitangcolHernan HuertaXu ZhangTomohiro NakamuraSergio Pablo SardiStuart A LiptonBrian K KennedyJuan Pablo HenriquezJ Cesar CárdenasLars PlateAdrián G PalaciosClaudio HetzPublished in: The EMBO journal (2022)
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.
Keyphrases
- endoplasmic reticulum
- cognitive decline
- endoplasmic reticulum stress
- signaling pathway
- cerebral ischemia
- resting state
- transcription factor
- white matter
- mild cognitive impairment
- single cell
- mouse model
- genome wide
- poor prognosis
- functional connectivity
- induced apoptosis
- dna damage
- endothelial cells
- stem cells
- epithelial mesenchymal transition
- gene expression
- pi k akt
- oxidative stress
- amino acid
- cell therapy
- cognitive impairment
- dna methylation
- copy number
- mesenchymal stem cells
- single molecule
- long non coding rna
- bioinformatics analysis