Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

Felipe Cabral-Miranda, Giovanni Tamburini, Gabriela Martinez, Alvaro O. Ardiles, Danilo B. Medinas, Yannis Gerakis, Mei Li Diaz Hung, René Vidal, Matias Fuentealba, Tim Miedema, Claudia Duran-Aniotz, Javier Diaz, Cristobal Ibaceta-Gonzalez, Carleen M. Sabusap, Francisca Bermedo-Garcia, Paula Mujica, Stuart Adamson, Kaitlyn Vitangcol, Hernan Huerta, Xu ZhangTomohiro Nakamura, Sergio Pablo Sardi, Stuart A. Lipton, Brian K. Kennedy, Juan Pablo Henriquez, J. Cesar Cárdenas, Lars Plate, Adrian G. Palacios, Claudio Hetz

Research output: Contribution to journalArticlepeer-review

Abstract

Aging is a major risk factor for 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 associated with synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Original languageEnglish
JournalEMBO Journal
DOIs
StateAccepted/In press - 2022
Externally publishedYes

Keywords

  • ER stress
  • UPR
  • XBP1s
  • aging brain
  • proteostasis

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