1. Control of mammalian brain ageing by the unfolded protein response transcription factor XBP1
- Author
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Xu Zhang, Cristobal Ibaceta Ibaceta-Gonzalez, Stuart A. Lipton, Stuart S. Adamson, Claudio Hetz, Claudia Duran-Aniotz, Carleen Sabusap, Giovanni Tamburini, Hernan Huerta, Adrian G. Palacios, Kaitlyn Vitangcol, Tomohiro Nakamura, Tim Miedema, Francisca Bermedo, Danilo B. Medinas, S. Pablo Sardi, Felipe Cabral-Miranda, Yannis Gerakis, Alvaro O. Ardiles, Julio Matus, Juan Pablo Henríquez, Gabriela Martínez, Lars Plate, and Brian K. Kennedy
- Subjects
XBP1 ,Ageing ,Chemistry ,Unfolded protein response ,Mammalian brain ,Transcription factor ,Cell biology - Abstract
Brain ageing is the main risk factor to develop dementia and neurodegenerative diseases, associated with a decay in the buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway to cope with ER stress, to the functional deterioration of the brain during aging. Genetic disruption of the ER stress sensor IRE1α accelerated cognitive and motor decline during ageing. Exogenous bolstering of the UPR by 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 indicated that XBP1s expression attenuated age-related alterations to synaptic function and pathways linked to neurodegenerative diseases. Overall, our results demonstrate that strategies to manipulate the UPR in mammals may sustain healthy brain ageing.
- Published
- 2020