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

被引：34

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

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