Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

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; Claudio Hetz

doi:10.15252/embj.2022111952

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

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 ZhangTomohiro Nakamura, Sergio Pablo Sardi, Stuart A. Lipton, Brian K. Kennedy, Juan Pablo Henriquez, J. Cesar Cárdenas, Lars Plate, Adrian G. Palacios, Claudio Hetz

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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.

Original language	English
Article number	e111952
Journal	EMBO Journal
Volume	41
Issue number	22
DOIs	https://doi.org/10.15252/embj.2022111952
State	Published - 17 Nov 2022
Externally published	Yes

Keywords

ER stress
UPR
XBP1s
aging brain
proteostasis

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10.15252/embj.2022111952

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Cabral-Miranda, F., Tamburini, G., Martinez, G., Ardiles, A. O., Medinas, D. B., Gerakis, Y., Hung, M. L. D., Vidal, R., Fuentealba, M., Miedema, T., Duran-Aniotz, C., Diaz, J., Ibaceta-Gonzalez, C., Sabusap, C. M., Bermedo-Garcia, F., Mujica, P., Adamson, S., Vitangcol, K., Huerta, H., ... Hetz, C. (2022). Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging. EMBO Journal, 41(22), Article e111952. https://doi.org/10.15252/embj.2022111952

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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 = "Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

month = nov,

day = "17",

doi = "10.15252/embj.2022111952",

language = "English",

volume = "41",

journal = "EMBO Journal",

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Cabral-Miranda, F, Tamburini, G, Martinez, G, Ardiles, AO, Medinas, DB, Gerakis, Y, Hung, MLD, Vidal, R, Fuentealba, M, Miedema, T, Duran-Aniotz, C, Diaz, J, Ibaceta-Gonzalez, C, Sabusap, CM, Bermedo-Garcia, F, Mujica, P, Adamson, S, Vitangcol, K, Huerta, H, Zhang, X, Nakamura, T, Sardi, SP, Lipton, SA, Kennedy, BK, Henriquez, JP, Cárdenas, JC, Plate, L, Palacios, AG & Hetz, C 2022, 'Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging', EMBO Journal, vol. 41, no. 22, e111952. https://doi.org/10.15252/embj.2022111952

TY - JOUR

T1 - Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

AU - Cabral-Miranda, Felipe

AU - Tamburini, Giovanni

AU - Martinez, Gabriela

AU - Ardiles, Alvaro O.

AU - Medinas, Danilo B.

AU - Gerakis, Yannis

AU - Hung, Mei Li Diaz

AU - Vidal, René

AU - Fuentealba, Matias

AU - Miedema, Tim

AU - Duran-Aniotz, Claudia

AU - Diaz, Javier

AU - Ibaceta-Gonzalez, Cristobal

AU - Sabusap, Carleen M.

AU - Bermedo-Garcia, Francisca

AU - Mujica, Paula

AU - Adamson, Stuart

AU - Vitangcol, Kaitlyn

AU - Huerta, Hernan

AU - Zhang, Xu

AU - Nakamura, Tomohiro

AU - Sardi, Sergio Pablo

AU - Lipton, Stuart A.

AU - Kennedy, Brian K.

AU - Henriquez, Juan Pablo

AU - Cárdenas, J. Cesar

AU - Plate, Lars

AU - Palacios, Adrian G.

AU - Hetz, Claudio

PY - 2022/11/17

Y1 - 2022/11/17

N2 - 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.

AB - 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.

KW - ER stress

KW - UPR

KW - XBP1s

KW - aging brain

KW - proteostasis

UR - http://www.scopus.com/inward/record.url?scp=85141150685&partnerID=8YFLogxK

U2 - 10.15252/embj.2022111952

DO - 10.15252/embj.2022111952

M3 - Article

C2 - 36314651

AN - SCOPUS:85141150685

SN - 0261-4189

VL - 41

JO - EMBO Journal

JF - EMBO Journal

IS - 22

M1 - e111952

ER -

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

Abstract

Keywords

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