Control of mammalian brain aging by the unfolded protein response (UPR)

Felipe Cabral‐Miranda; Giovanni Tamburini; Gabriela Martínez; Álvaro O. Ardiles; Danilo B. Medinas; Yannis Gerakis; Mei-Li Díaz Hung; René L. Vidal; Matías Fuentealba; Tim Miedema; Claudia A. Duran-Aniotz; Javier Diaz; Cristobal Ibaceta-González; Carleen Mae P. Sabusap; Francisca Bermedo‐García; Paula Mujica; Stuart S. Adamson; Kaitlyn Vitangcol; Hernán Huerta; Xu Zhang; Tomohiro Nakamura; S. Pablo Sardi; Stuart A. Lipton; Brian Keith Kennedy; Juan Pablo Henríquez; César Cárdenas; Lars Plate; Adrián G. Palacios; Claudio A. Hetz

doi:10.15252/embj.2022111952

NeuroscienceThe EMBO JournalOct 31, 2022

Peer-reviewed journal article

Control of mammalian brain aging by the unfolded protein response (UPR)

Felipe Cabral‐Miranda iD, Giovanni Tamburini, Gabriela Martínez, Álvaro O. Ardiles iD, Danilo B. Medinas iD, Yannis Gerakis, Mei-Li Díaz Hung, René L. Vidal iD, Matías Fuentealba iD, Tim Miedema iD, Claudia A. Duran-Aniotz iD, Javier Diaz, Cristobal Ibaceta-González iD, Carleen Mae P. Sabusap iD, Francisca Bermedo‐García iD, Paula Mujica, Stuart S. Adamson iD, Kaitlyn Vitangcol, Hernán Huerta iD, Xu Zhang iD, Tomohiro Nakamura iD, S. Pablo Sardi iD, Stuart A. Lipton iD, Brian Keith Kennedy iD, Juan Pablo Henríquez iD, , Claudio A. Hetz iD

Abstract

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1 accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging. One Sentence SummaryThe IRE1/XBP1 pathway dictates when and how brain function declines during aging.

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