Research progress of integrated stress response in pathogenesis of Alzheimer's disease
SUN Hui,, JIN Hongfu, GUO Shenrui, FENG Yiyuan, YIN Yafu, WANG Hui, CHENG Weiwei,
Department of Nuclear Medicine/Institute of Cardiovascular Development and Regenerative Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Integrated stress response (ISR) is a cellular adaptive response induced by stress, which is strictly regulated by multiple phosphokinases, phosphatases and other proteins to maintain protein homeostasis. Studies have shown that ISR is abnormally activated in Alzheimer's disease, and targeted regulation of different proteins in ISR pathway inhibits the abnormal activation of ISR, leading to restoration of protein homeostasis and alleviation of the neuropathological changes and memory impairment in Alzheimer's disease models. These lines of evidence suggest that ISR has the potential to be a therapeutic target in Alzheimer's disease treatment. This paper reviews the abnormal activation and regulation mechanism of ISR in Alzheimer's disease and discusses the application of ISR as therapeutic targets to Alzheimer's disease models.
SUN Hui, JIN Hongfu, GUO Shenrui, FENG Yiyuan, YIN Yafu, WANG Hui, CHENG Weiwei. Research progress of integrated stress response in pathogenesis of Alzheimer's disease. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(6): 755-760 doi:10.3969/j.issn.1674-8115.2023.06.012
在包括AD、帕金森病、肌萎缩侧索硬化症等多种神经退行性疾病的患者及动物模型中均存在ISR异常激活。据研究［4］报道，消融性白质脑病（vanishing white matter disease，VWMD）患者存在eIF2B亚基突变，突变的eIF2B活性下降导致TC浓度降低，表现为ISR过度激活，导致疾病发生。在其他疾病包括肿瘤［8-9］及心血管疾病［10］中，ISR过度激活也被证实在疾病发生和发展中发挥重要作用。反之，ISR过度抑制同样会引起疾病发生，如eIF2α磷酸化位点突变致使ISR过度抑制，可导致小鼠缺乏胰腺β细胞并在出生后18 h内死于低血糖［11］。这些证据提示ISR活性水平的精准调控对于机体生长发育及维持健康至关重要。
The topic selection and writing instruction were performed by CHENG Weiwei. The manuscript was drafted and revised by SUN Hui, JIN Hongfu, GUO Shenrui, FENG Yiyuan,YIN Yafu, and WANG Hui. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
All authors disclose no relevant conflict of interests.
GBD 2019 DEMENTIA FORECASTING COLLABORATORS. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019[J]. Lancet Public Health, 2022, 7(2): e105-e125.
HARDING H P, ZHANG Y, ZENG H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress[J]. Mol Cell, 2003, 11(3): 619-633.
ALGIRE M A, MAAG D, LORSCH J R. Pi release from eIF2, not GTP hydrolysis, is the step controlled by start-site selection during eukaryotic translation initiation[J]. Mol Cell, 2005, 20(2): 251-262.
KENNER L R, ANAND A A, NGUYEN H C, et al. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response[J]. Science, 2019, 364(6439): 491-495.
OLIVEIRA M M, KLANN E. eIF2-dependent translation initiation: memory consolidation and disruption in Alzheimer's disease[J]. Semin Cell Dev Biol, 2022, 125:101-109.
GARCÍA-JIMÉNEZ C, GODING C R. Starvation and pseudo-starvation as drivers of cancer metastasis through translation reprogramming[J]. Cell Metab, 2019, 29(2): 254-267.
VERGINADIS I I, AVGOUSTI H, MONSLOW J, et al. A stromal integrated stress response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression[J]. Nat Cell Biol, 2022, 24(6): 940-953.
CHATTOPADHYAY A, KWARTLER C S, KAW K, et al. Cholesterol-induced phenotypic modulation of smooth muscle cells to macrophage/fibroblast-like cells is driven by an unfolded protein response[J]. Arterioscler Thromb Vasc Biol, 2021, 41(1): 302-316.
SCHEUNER D, SONG B, MCEWEN E, et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis[J]. Mol Cell,2001,7(6):1165-1176.
SANTOS-RIBEIRO D, GODINAS L, PILETTE C, et al. The integrated stress response system in cardiovascular disease[J]. Drug Discov Today, 2018, 23(4): 920-929.
MORADI MAJD R, MAYELI M, RAHMANI F. Pathogenesis and promising therapeutics of Alzheimer disease through eIF2α pathway and correspondent kinases[J]. Metab Brain Dis, 2020, 35(8): 1241-1250.
MA T, TRINH M A, WEXLER A J, et al. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits[J]. Nat Neurosci, 2013, 16(9): 1299-1305.
TIBLE M, MOUTON LIGER F, SCHMITT J, et al. PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions[J]. Aging Cell, 2019, 18(3): e12887.
WONG Y L, LEBON L, BASSO A M, et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response[J]. Elife, 2019, 8: e42940.
NOVOA I, ZENG H, HARDING H P, et al. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α[J]. J Cell Biol, 2001, 153(5): 1011-1022.
JAWAID A, WOLDEMICHAEL B T, KREMER E A, et al. Memory decline and its reversal in aging and neurodegeneration involve miR-183/96/182 biogenesis[J]. Mol Neurobiol, 2019, 56(5): 3451-3462.
CHANG R C, WONG A K, NG H K, et al. Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease[J]. Neuroreport, 2002, 13(18): 2429-2432.
O'CONNOR T, SADLEIR K R, MAUS E, et al. Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis[J]. Neuron, 2008, 60(6): 988-1009.
HU Z, YU P, ZHANG Y, et al. Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of Alzheimer's disease[J]. Transl Psychiatry, 2022, 12(1): 96.
RADFORD H, MORENO J A, VERITY N, et al. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia[J]. Acta Neuropathol, 2015, 130(5): 633-642.
OLIVEIRA M M, LOURENCO M V. Integrated stress response: connecting ApoE4 to memory impairment in Alzheimer's disease[J]. J Neurosci, 2016, 36(4): 1053-1055.
KASAI S, YAMAZAKI H, TANJI K, et al. Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control[J]. J Clin Biochem Nutr, 2019, 64(1): 1-12.
LOPEZ-GRANCHA M, BERNARDELLI P, MOINDROT N, et al. A novel selective PKR inhibitor restores cognitive deficits and neurodegeneration in Alzheimer disease experimental models[J]. J Pharmacol Exp Ther, 2021, 378(3): 262-275.
LI J, GAO L, CHEN J, et al. Mitochondrial ROS-mediated ribosome stalling and GCN2 activation are partially involved in 1-nitropyrene-induced steroidogenic inhibition in testes[J]. Environ Int, 2022, 167: 107393.
RABOUW H H, LANGEREIS M A, ANAND A A, et al. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation[J]. Proc Natl Acad Sci USA, 2019, 116(6): 2097-2102.
OLIVEIRA M M, LOURENCO M V, LONGO F, et al. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease[J]. Sci Signal, 2021, 14(668): eabc5429.
TSAYTLER P, HARDING H P, RON D, et al. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis[J]. Science, 2011, 332(6025): 91-94.
SINGH A, GUPTA P, TIWARI S, et al. Guanabenz mitigates the neuropathological alterations and cell death in Alzheimer's disease[J]. Cell Tissue Res, 2022, 388(2): 239-258.
RUIZ A, ZUAZO J, ORTIZ-SANZ C, et al. Sephin1 protects neurons against excitotoxicity independently of the integrated stress response[J]. Int J Mol Sci, 2020, 21(17): E6088.
CARRARA M, SIGURDARDOTTIR A, BERTOLOTTI A. Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors[J]. Nat Struct Mol Biol, 2017, 24(9): 708-716.
