微小RNA在tau蛋白过度磷酸化中的作用
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摘要
阿尔茨海默病(Alzheimer’s Disease, AD)是一种慢性神经系统退行性疾病,AD的主要病理表现为脑组织中的老年斑和神经纤维缠结,老年斑的主要成分是异常积聚的β-淀粉样蛋白,过度磷酸化的tau蛋白是神经纤维缠结的主要成分。研究发现AD患者脑内微小RNA表达异常,且证据表明微小RNA参与β-淀粉样蛋白过量生成和tau蛋白过度磷酸化等Alzheimer样病理机制,在AD的发病中起着重要作用。本文就微小RNA在tau蛋白过度磷酸化中的作用及机制进行概述。
Alzheimer's disease(AD) is a chronic neurodegenerative disease. The main pathological manifestations of AD are senile plaques and neurofibrillary tangles in brain tissue. The main component of senile plaques is abnormal accumulation of β-amyloid(Aβ) and the main component of neurofibrillary tangles is hyperphosphorylated tau protein. It has been found that the abnormal expression of microRNA in the brain of AD patients is involved in the Alzheimer-like pathological mechanisms including overproduction of Aβ and hyperphosphorylation of tau protein, which plays an important role in the pathogenesis of AD. This article summarizes the mechanism and role of microRNAs in the hyperphosphorylation of tau protein.
Alzheimer's disease(AD) is a chronic neurodegenerative disease. The main pathological manifestations of AD are senile plaques and neurofibrillary tangles in brain tissue. The main component of senile plaques is abnormal accumulation of β-amyloid(Aβ) and the main component of neurofibrillary tangles is hyperphosphorylated tau protein. It has been found that the abnormal expression of microRNA in the brain of AD patients is involved in the Alzheimer-like pathological mechanisms including overproduction of Aβ and hyperphosphorylation of tau protein, which plays an important role in the pathogenesis of AD. This article summarizes the mechanism and role of microRNAs in the hyperphosphorylation of tau protein.
引文
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[3]Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell, 2009, 136(4):642-655.
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[12] EI Fatimy R, Li S, Chen Z, et al. MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways. Acta Neuropathol, 2018, 136(4):537-555.
[13] Choi J, Levey AI, Weintraub ST, et al. Oxidative modificationsanddown-regulationofubiquitincarboxyl-terminal hydrolaseL1associatedwithidiopathicParkinson’sand Alzheimer’s disease. J Biol Chem, 2004, 279(13):13256-13264.
[14] Zhao ZB, Wu L, Xiong R, et al. MicroRNA-922 promotes tauphosphorylationbydownregulatingubiquitincarboxy-terminalhydrolaseL1(UCHL1)expressioninthe pathogenesis of Alzheimer’s disease. Neuroscience, 2014,275:232-237.
[15] Wang G, Huang Y, Wang LL, et al. MicroRNA-146a suppressesROCK1allowinghyperphosphorylationoftauin Alzheimer’s disease. Sci Rep, 2016, 6:26697.
[16] Hébert SS, Sergeant N, Buée L. MicroRNAs and the Regulation of Tau Metabolism. Int J Alzheimers Dis, 2012, 2012:406561.
[17] Zamore PD, Haley B. Ribo-gnome:the big world of small RNAs. Science, 2005, 309(5740):1519-1524.
[18] DicksonJR,KruseC,MontagnaDR,etal. Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem, 2013, 127(6):739-749.
[19] Hernández F, Avila J. Tauopathies. Cell Mol Life Sci, 2007,64(17):2219-2233.
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[21] Jafarnejad SM, Chapat C, Matta-Camacho E, et al. Translational control of ERK signaling through miRNA/4EHP-directed silencing. Elife, 2018, 7:e35034.
[22] Zhang Z, Kobayashi S, Borczuk AC, et al. Dual specificity phosphatase 6(DUSP6)is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis, 2010, 31(4):577-586.
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[24] Patrick GN, Zukerberg L, Nikolic M, et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 1999, 402(6762):615-622.
[25] Absalon S, Kochanek DM, Raghavan V, et al. MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry,tau-phosphorylation, and apoptosis in postmitotic neurons.J Neurosci, 2013, 33(37):14645-14659.
[26] Sun LH, Ban T, Liu CD, et al. Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation. J Neurochem, 2015, 134(6):1139-1151.
[27] Wang Y, Veremeyko T, Wong AH, et al. Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer’s disease. Neurobiol Aging, 2017, 51:156-166.
[28] Kaytor MD, Orr HT. The GSK3 beta signaling cascade and neurodegenerativedisease.CurrOpinNeurobiol,2002,12(3):275-278.
[29] Wang X, Tan L, Lu Y, et al. MicroRNA-138 promotes tau phosphorylation by targeting retinoic acid receptor alpha.FEBS Lett, 2015, 589(6):726-729.
[30] Kang Q, Xiang Y, Li D, et al. MiR-124-3p attenuates hyperphosphorylationof Tauprotein-inducedapoptosisvia caveolin-1-PI3K/AKt/GSK3βpathway in N2a/APP695swe cells. Oncotarget, 2017, 8(15):24314-24326.
[31] Deters N, Ittner LM, G?tz J. Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochem Biophys Res Commun, 2009, 379(2):400-405.
[32] GongCX,Lidsky T, WegielJ,etal.Phosphorylationof microtubule-associated protein tau is regulated by protein phosphatase2Ainmammalianbrain.Implicationsfor neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem, 2000, 275(8):5535-5544.
[33] Corder EH, Ghebremedhin E, Taylor MG, et al. The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions:modification by age, sex,and APOE polymorphism. Ann N Y Acad Sci, 2004, 1019:24-28.
[34] Xiong YS, Liu FF, Liu D, et al. Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway. Aging Cell, 2015,14(5):867-877.
[35] Smith PY, Hernandez-Rapp J, Jolivette F, et al. MiR-132/212deficiency impairs tau metabolism and promotes pathologicalaggregationinvivo.HumMolGenet,2015,24(23):6721-6735.
[2]Selkoe DJ. Cell biology of protein misfolding:the examples of Alzheimer’sandParkinson’sdiseases.NatCellBiol,2004, 6(11):1054-1061.
[3]Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell, 2009, 136(4):642-655.
[4]Huang Y, Mucke L. Alzheimer mechanisms and therapeutic straegies. Cell, 2012, 148(6):1204-1222.
[5]DermautB,Kumar-SinghS,RademakersR,etal. Tauis central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet, 2005, 21(12):664-672.
[6]Alonso AD,Grundke-IqbalI,BarraHS,etal. Abnormal phosphorylationoftauandthemechanismof Alzheimer neurofibrillarydegeneration:sequestrationofmicrotubule-associatedproteins1and2andthedisassemblyof microtubules by the abnormal tau. Proc Natl Acad Sci U S A,1997, 94(1):298-303.
[7]Mocanu MM, Nissen A, Eckermann K, et al. The potential for beta-structure in the repeat domain of tau protein in determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci, 2008, 28(3):737-748.
[8]QureshiIA,MehlerMF.Emergingrolesofnon-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci, 2012, 13(8):528-541.
[9]Schonrock N, Ke YD, Humphreys D, et al. Neuronal microRNAderegulationinresponseto Alzheimer’sdisease amyloid-beta. PLoS One, 2010, 5(6):e11070.
[10] Scott-McKean JJ, Surewicz K, Choi JK, et al. Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aβoligomers:Implications for novel therapeutic strategy in Alzheimer’s disease. Neurobiol Dis,2016, 91:124-131.
[11] Banzhaf-SrtathmannJ,BentioE,MayS,etal.MicroRNA-125b induces tau hyperphosphorylation and cognitive deficitsin Alzheimer’sdisease.EMBOJ,2014,33(15):1667-1680.
[12] EI Fatimy R, Li S, Chen Z, et al. MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways. Acta Neuropathol, 2018, 136(4):537-555.
[13] Choi J, Levey AI, Weintraub ST, et al. Oxidative modificationsanddown-regulationofubiquitincarboxyl-terminal hydrolaseL1associatedwithidiopathicParkinson’sand Alzheimer’s disease. J Biol Chem, 2004, 279(13):13256-13264.
[14] Zhao ZB, Wu L, Xiong R, et al. MicroRNA-922 promotes tauphosphorylationbydownregulatingubiquitincarboxy-terminalhydrolaseL1(UCHL1)expressioninthe pathogenesis of Alzheimer’s disease. Neuroscience, 2014,275:232-237.
[15] Wang G, Huang Y, Wang LL, et al. MicroRNA-146a suppressesROCK1allowinghyperphosphorylationoftauin Alzheimer’s disease. Sci Rep, 2016, 6:26697.
[16] Hébert SS, Sergeant N, Buée L. MicroRNAs and the Regulation of Tau Metabolism. Int J Alzheimers Dis, 2012, 2012:406561.
[17] Zamore PD, Haley B. Ribo-gnome:the big world of small RNAs. Science, 2005, 309(5740):1519-1524.
[18] DicksonJR,KruseC,MontagnaDR,etal. Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem, 2013, 127(6):739-749.
[19] Hernández F, Avila J. Tauopathies. Cell Mol Life Sci, 2007,64(17):2219-2233.
[20] Hébert SS, Papadopoulou AS, Smith P, et al. Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum Mol Genet, 2010, 19(20):3959-3969.
[21] Jafarnejad SM, Chapat C, Matta-Camacho E, et al. Translational control of ERK signaling through miRNA/4EHP-directed silencing. Elife, 2018, 7:e35034.
[22] Zhang Z, Kobayashi S, Borczuk AC, et al. Dual specificity phosphatase 6(DUSP6)is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis, 2010, 31(4):577-586.
[23]陈操,田婵,赵玉军,等.tau蛋白异常翻译后修饰在阿尔茨海默病中的作用.医学分子生物学杂志,2009,6(1):56-59.
[24] Patrick GN, Zukerberg L, Nikolic M, et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 1999, 402(6762):615-622.
[25] Absalon S, Kochanek DM, Raghavan V, et al. MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry,tau-phosphorylation, and apoptosis in postmitotic neurons.J Neurosci, 2013, 33(37):14645-14659.
[26] Sun LH, Ban T, Liu CD, et al. Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation. J Neurochem, 2015, 134(6):1139-1151.
[27] Wang Y, Veremeyko T, Wong AH, et al. Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer’s disease. Neurobiol Aging, 2017, 51:156-166.
[28] Kaytor MD, Orr HT. The GSK3 beta signaling cascade and neurodegenerativedisease.CurrOpinNeurobiol,2002,12(3):275-278.
[29] Wang X, Tan L, Lu Y, et al. MicroRNA-138 promotes tau phosphorylation by targeting retinoic acid receptor alpha.FEBS Lett, 2015, 589(6):726-729.
[30] Kang Q, Xiang Y, Li D, et al. MiR-124-3p attenuates hyperphosphorylationof Tauprotein-inducedapoptosisvia caveolin-1-PI3K/AKt/GSK3βpathway in N2a/APP695swe cells. Oncotarget, 2017, 8(15):24314-24326.
[31] Deters N, Ittner LM, G?tz J. Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochem Biophys Res Commun, 2009, 379(2):400-405.
[32] GongCX,Lidsky T, WegielJ,etal.Phosphorylationof microtubule-associated protein tau is regulated by protein phosphatase2Ainmammalianbrain.Implicationsfor neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem, 2000, 275(8):5535-5544.
[33] Corder EH, Ghebremedhin E, Taylor MG, et al. The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions:modification by age, sex,and APOE polymorphism. Ann N Y Acad Sci, 2004, 1019:24-28.
[34] Xiong YS, Liu FF, Liu D, et al. Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway. Aging Cell, 2015,14(5):867-877.
[35] Smith PY, Hernandez-Rapp J, Jolivette F, et al. MiR-132/212deficiency impairs tau metabolism and promotes pathologicalaggregationinvivo.HumMolGenet,2015,24(23):6721-6735.
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