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

被引：33

作者：

Cabral-Miranda, Felipe ^{[1
,2
,3
,4
]}

Tamburini, Giovanni ^{[1
,2
,3
]}

Martinez, Gabriela ^{[1
,2
,3
]}

Ardiles, Alvaro O. ^{[5
,6
]}

Medinas, Danilo B. ^{[1
,2
,3
]}

Gerakis, Yannis ^{[1
,2
,3
]}

Hung, Mei-Li Diaz ^{[1
,2
,3
]}

Vidal, Rene ^{[1
,2
,7
]}

Fuentealba, Matias ^{[1
,2
,3
]}

Miedema, Tim ^{[1
,2
,3
]}

Duran-Aniotz, Claudia ^{[1
,2
,3
]}

Diaz, Javier ^{[1
,2
,3
]}

Ibaceta-Gonzalez, Cristobal ^{[5
]}

Sabusap, Carleen M. ^{[8
,9
]}

Bermedo-Garcia, Francisca ^{[10
]}

Mujica, Paula ^{[6
]}

Adamson, Stuart ^{[11
]}

Vitangcol, Kaitlyn ^{[11
]}

Huerta, Hernan ^{[7
]}

Zhang, Xu ^{[12
,13
]}

Nakamura, Tomohiro ^{[12
,13
]}

Sardi, Sergio Pablo ^{[14
]}

Lipton, Stuart A. ^{[12
,13
,15
]}

Kennedy, Brian K. ^{[11
,16
,17
,18
,19
]}

Pablo Henriquez, Juan ^{[10
]}

Cesar Cardenas, J. ^{[1
,7
,11
]}

Plate, Lars ^{[8
,9
]}

Palacios, Adrian G. ^{[5
]}

Hetz, Claudio ^{[1
,2
,3
,11
]}

机构：

[1] Ctr Gerosci Brain Hlth & Metab, Santiago, Chile

[2] Univ Chile, Fac Med, Biomed Neurosci Inst, Santiago, Chile

[3] Univ Chile, Fac Med, Inst Biomed Sci, Program Cellular & Mol Biol, Santiago, Chile

[4] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Rio De Janeiro, Brazil

[5] Univ Valparaiso, Ctr Interdisciplinario Neurociencia Valparaiso, Valparaiso, Chile

[6] Univ Valparaiso, Ctr Neurol Traslac, Escuela Med, Valparaiso, Chile

[7] Univ Mayor, Ctr Integrat Biol, Santiago, Chile

[8] Vanderbilt Univ, Dept Chem, Nashville, TN USA

[9] Vanderbilt Univ, Dept Biol Sci, Nashville, TN USA

[10] Univ Concepcion, Ctr Adv Microscopy CMA BioBio, Dept Cell Biol, Concepcion, Chile

[11] Buck Inst Res Aging, Novato, CA 94945 USA

[12] Scripps Res Inst, Dept Mol Med, La Jolla, CA USA

[13] Scripps Res Inst, Neurodegenerat New Med Ctr, La Jolla, CA USA

[14] Sanofi, Rare & Neurol Dis Therapeut Area, Framingham, MA USA

[15] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA USA

[16] Natl Univ Singapore, Yong Loo Lin Sch Med, Hlth Longev Translat Res Programme, Singapore, Singapore

[17] Natl Univ Singapore, Ctr Hlth Longev, Natl Univ Hlth Syst, Singapore, Singapore

[18] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore

[19] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore, Singapore

来源：

EMBO JOURNAL | 2022年 / 41卷 / 22期

关键词：

aging brain; ER stress; proteostasis; UPR; XBP1s; ER STRESS; NEUROTROPHIC FACTOR; EIF2-ALPHA KINASES; MEMORY; ACTIVATION; PROTEOSTASIS; SENESCENCE; XBP1; METABOLISM; RESISTANCE;

D O I：

10.15252/embj.2022111952

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Aging is a major risk factor for 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 associated with synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

引用

页数：21

共 50 条

[21] IRE1α-XBP1 in leukocytes mediates pain
不详
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2020, 140 (07) : 1304 - 1304
[22] IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis
Tohmonda, Takahide
Yoda, Masaki
Iwawaki, Takao
Matsumoto, Mono
Nakamura, Masaya
Mikoshiba, Katsuhiko
Toyama, Yoshiaki
Horiuchi, Keisuke
JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (08): : 3269 - 3279
[23] Type 1 calreticulin mutations differentially activate the IRE1α-XBP1 pathway of the unfolded protein response to drive myeloproliferative neoplasms.
Ibarra, Juan
Elbanna, Yassmin
Kurylowicz, Katarzyna
Ciboddo, Michele
Greenbaum, Harrison S.
Arellano, Nicole S.
Rodriguez, Deborah
Evers, Maria
Yang, Dongbo
Bock-Hughes, Althea
Liu, Chenyu
Smith, Quinn
Baumeister, Julian
Kalmer, Milena
Olschok, Kathrin
Nicholson, Benjamin
Silva, Diane
Dowgielewicz, Jonathan
Rumi, Elisa
Pietra, Daniela
Casetti, Ilaria Carola
Koschmieder, Steffen
Gurbuxani, Sandeep
Schneider, Rebekka K.
Oakes, Scott A.
Elf, Shannon E.
CANCER RESEARCH, 2022, 82 (12)
[24] Unfolded protein response transducer IRE1-mediated signaling independent of XBP1 mRNA splicing is not required for growth and development of medaka fish
Ishikawa, Tokiro
Kashima, Makoto
Nagano, Atsushi J.
Ishikawa-Fujiwara, Tomoko
Kamei, Yasuhiro
Todo, Takeshi
Mori, Kazutoshi
ELIFE, 2017, 6
[25] IRE1 α-XBP1 signaling pathway, a potential therapeutic target in multiple myeloma
Chen, Lin
Li, Qian
She, Tiantian
Li, Han
Yue, Yuanfang
Gao, Shuang
Yan, Tinghui
Liu, Su
Ma, Jing
Wang, Yafei
LEUKEMIA RESEARCH, 2016, 49 : 7 - 12
[26] Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms
Ibarra, Juan
Elbanna, Yassmin A.
Kurylowicz, Katarzyna
Ciboddo, Michele
Greenbaum, Harrison S.
Arellano, Nicole S.
Rodriguez, Deborah
Evers, Maria
Bock-Hughes, Althea
Liu, Chenyu
Smith, Quinn
Lutze, Julian
Baumeister, Julian
Kalmer, Milena
Olschok, Kathrin
Nicholson, Benjamin
Silva, Diane
Maxwell, Luke
Dowgielewicz, Jonathan
Rumi, Elisa
Pietra, Daniela
Casetti, Ilaria Carola
Catricala, Silvia
Koschmieder, Steffen
Gurbuxani, Sandeep
Schneider, Rebekka K.
Oakes, Scott A.
Elf, Shannon E.
BLOOD CANCER DISCOVERY, 2022, 3 (04): : 298 - 315
[27] ER stress signaling by regulated splicing:: IRE1/HAC1/XBP1
Back, SH
Schröder, M
Lee, K
Zhang, KZ
Kaufman, RJ
METHODS, 2005, 35 (04) : 395 - 416
[28] Functional analysis of the mammalian RNA ligase for IRE1 in the unfolded protein response
Poothong, Juthakorn
Tirasophon, Witoon
Kaufman, Randal J.
BIOSCIENCE REPORTS, 2017, 37
[29] The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle
Joshi, Aniket S.
da Silva, Meiricris Tomaz
Roy, Anirban
Koike, Tatiana E.
Wu, Mingfu
Castillo, Micah B.
Gunaratne, Preethi H.
Liu, Yu
Iwawaki, Takao
Kumar, Ashok
EMBO REPORTS, 2024, 25 (08) : 3627 - 3650
[30] Targeting the IRE1α/XBP1 and ATF6 Arms of the Unfolded Protein Response Enhances VEGF Blockade to Prevent Retinal and Choroidal Neovascularization
Liu, Li
Qi, Xiaoping
Chen, Zhijuan
Shaw, Lynn
Cai, Jun
Smith, Layton H.
Grant, Maria B.
Boulton, Michael E.
AMERICAN JOURNAL OF PATHOLOGY, 2013, 182 (04): : 1412 - 1424

← 1 2 3 4 5 →