1. Unfolded protein response <scp>IRE1</scp> / <scp>XBP1</scp> signaling is required for healthy mammalian brain aging
- Author
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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 Zhang, Tomohiro Nakamura, Sergio Pablo Sardi, Stuart A Lipton, Brian K Kennedy, Juan Pablo Henriquez, J Cesar Cárdenas, Lars Plate, Adrian G Palacios, and Claudio Hetz
- Subjects
Proteomics ,X-Box Binding Protein 1 ,Aging ,General Immunology and Microbiology ,General Neuroscience ,Brain ,Protein Serine-Threonine Kinases ,Endoplasmic Reticulum Stress ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Unfolded Protein Response ,Animals ,Molecular Biology ,Signal Transduction - 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.
- Published
- 2022
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