Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 31, 2022
- Source ID
- 10.15252/embj.2022111952
Entities
People
- Adrian G Palacios
- Alvaro O Ardiles
- Brian K. Kennedy
- Carleen M Sabusap
- Claudia Duran‐aniotz
- Claudio Hetz
- Cristobal Ibaceta‐gonzalez
- Danilo B. Medinas
- Felipe Cabral‐miranda
- Francisca Bermedo‐garcia
- Gabriela Martínez
- Giovanni Tamburini
- Hernan Huerta
- J Cesar Cárdenas
- Javier Diaz
- Juan Pablo Henriquez
- Kaitlyn Vitangcol
- Lars Plate
- Matias Fuentealba
- Mei‐li Diaz Hung
- Paula Mujica
- René Vidal
- S Pablo Sardi
- Stuart A. Lipton
- Stuart Adamson
- Tim Miedema
- Tomohiro Nakamura
- Xu Zhang
- Yannis Gerakis
Organizations
- Buck Institute for Research on Aging
- European Commission
- Federal University of Rio de Janeiro
- Foundation for the National Institutes of Health
- National Fund for Scientific and Technological Development
- Sanofi
- United States Air Force
- University of California, San Diego
- University of Valparaíso
- Vanderbilt University