@article{b6568fe003b74a6f9ecc0d92bd91a0e9,
title = "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.",
keywords = "ER stress, UPR, XBP1s, aging brain, proteostasis",
author = "Felipe Cabral-Miranda and Giovanni Tamburini and Gabriela Martinez and Ardiles, {Alvaro O.} and Medinas, {Danilo B.} and Yannis Gerakis and Hung, {Mei Li Diaz} and Ren{\'e} Vidal and Matias Fuentealba and Tim Miedema and Claudia Duran-Aniotz and Javier Diaz and Cristobal Ibaceta-Gonzalez and Sabusap, {Carleen M.} and Francisca Bermedo-Garcia and Paula Mujica and Stuart Adamson and Kaitlyn Vitangcol and Hernan Huerta and Xu Zhang and Tomohiro Nakamura and Sardi, {Sergio Pablo} and Lipton, {Stuart A.} and Kennedy, {Brian K.} and Henriquez, {Juan Pablo} and C{\'a}rdenas, {J. Cesar} and Lars Plate and Palacios, {Adrian G.} and Claudio Hetz",
note = "Funding Information: We thank Dr. Takao Iwawaki for providing IRE1α null animals. We thank Javiera Ponce, Francisco Aburto and Diego Rivas for animal care. We also thank Monica Flores and Maria Painavel for technical support. FONDECYT 1220573 (CH). FONDAP program 15150012 (CH). Millennium Institute Initiative P09‐015‐F and P09‐022‐F (CH). European Commission R&D MSCA‐RISE 734749 (CH). FONDEF ID16I10223 (CH) and ID22110120. Department of Defense USA grant W81XWH2110960 PD200085 (CH). U.S. Air Force Office of Scientific Research grant FA9550‐16‐1‐0384 (CH). Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (CONICYT)‐CNP1q 441921/2016‐7 (CH). FONDECYT 1170614 (JPH). FONDECYT 11160760 (CDA). Postdoctoral fellowships: FONDECYT 3180195 (FCM) and FONDECYT 3080702 (YG), 3190596 (MLD), 1191003, and 1191538. Conicyt ‐ REDI170583 (CDA). FONDECYT 11150776 (AOA). FONDECYT (RV). NIH: R35 AG071734, R01 NS086890, R01 DA048882, DP1 DA041722, RF1 AG057409, and R01 AG056259 (to SAL), R01 AG061845 (to TN), R35 GM133552 (to LP). Funding Information: We thank Dr. Takao Iwawaki for providing IRE1α null animals. We thank Javiera Ponce, Francisco Aburto and Diego Rivas for animal care. We also thank Monica Flores and Maria Painavel for technical support. FONDECYT 1220573 (CH). FONDAP program 15150012 (CH). Millennium Institute Initiative P09-015-F and P09-022-F (CH). European Commission R&D MSCA-RISE 734749 (CH). FONDEF ID16I10223 (CH) and ID22110120. Department of Defense USA grant W81XWH2110960 PD200085 (CH). U.S. Air Force Office of Scientific Research grant FA9550-16-1-0384 (CH). Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (CONICYT)-CNP1q 441921/2016-7 (CH). FONDECYT 1170614 (JPH). FONDECYT 11160760 (CDA). Postdoctoral fellowships: FONDECYT 3180195 (FCM) and FONDECYT 3080702 (YG), 3190596 (MLD), 1191003, and 1191538. Conicyt - REDI170583 (CDA). FONDECYT 11150776 (AOA). FONDECYT (RV). NIH: R35 AG071734, R01 NS086890, R01 DA048882, DP1 DA041722, RF1 AG057409, and R01 AG056259 (to SAL), R01 AG061845 (to TN), R35 GM133552 (to LP). Publisher Copyright: {\textcopyright} 2022 The Authors.",
year = "2022",
month = nov,
day = "17",
doi = "10.15252/embj.2022111952",
language = "English",
volume = "41",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Wiley-Blackwell",
number = "22",
}