Wnt信号通路与神经发生、神经退行性变过程中的表述及作用
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摘要
背景:Wnt信号通路作为一条多环节、多作用位点的开放通路,在神经系统中发挥着非常重要的作用,因此,了解其与神经系统疾病的病理生理机制和治疗的关系有重要意义。目的:分析Wnt信号通路在神经系统疾病中的作用机制。方法:应用计算机检索PubMed、SinoMed等数据库有关Wnt信号通路、神经系统疾病相关的文献,检索词为"Wnt signaling pathway,Nervous system disease,阿尔茨海默病,帕金森病;Wnt信号通路,神经系统疾病",最终筛选出具有代表性的62篇作为研究对象。结果与结论:无论是在阿尔茨海默病、帕金森病、还是在脑血管病等神经系统疾病中均有Wnt信号通路的参与。但Wnt信号通路在各神经系统疾病中发挥的作用并不相同,比如Wnt信号通路功能的缺失使得神经元形成能力下降,直接导致阿尔茨海默病病程加快。Wnt信号通路调控多巴胺能神经元新生、细胞存活、突触发生,从而影响帕金森病发生发展。因此,了解Wnt信号中各配体、受体及基因在神经系统疾病存在的互作关系,有利于Wnt信号通路在神经系统疾病的基础研究的开展,同时对于发现治疗神经系统疾病靶点有重要的临床意义。
BACKGROUND: Wnt signaling pathway plays an important role in the nervous system as a multi-link and multi-site open pathway. Therefore, it is important to understand its relationship with the pathophysiology and treatment of neurological diseases. OBJECTIVE: To analyze the mechanism of Wnt signaling pathway in nervous system diseases.METHODS: PubMed and Sino Med were searched for the relevant articles concerning Wnt signaling pathway and nervous system diseases. The key words were "Wnt signaling pathway, nervous system disease" in English and Chinese, respectively. Finally, 62 pertinent articles were included for result analysis. RESULTS AND CONCLUSION: Wnt signaling pathway is involved in Alzheimer's disease, Parkinson's disease and cerebrovascular disease. However, its role is different in different neurological diseases. For example, the dysfunction of Wnt signaling pathway leads to the disability of neuronal formation, which accelerates the progression of Alzheimer's disease. Besides, Wnt signaling pathway regulates the proliferation of dopaminergic neurons, cell survival and synaptogenesis, thus affecting the development of Parkinson's disease. Therefore, understanding the interaction between ligands, receptors and genes in Wnt signaling pathway in nervous system diseases is conducive to the development of Wnt signaling in the basic research of neurological diseases, and is of great significance for searching for the treatment targets of nervous system diseases.
BACKGROUND: Wnt signaling pathway plays an important role in the nervous system as a multi-link and multi-site open pathway. Therefore, it is important to understand its relationship with the pathophysiology and treatment of neurological diseases. OBJECTIVE: To analyze the mechanism of Wnt signaling pathway in nervous system diseases.METHODS: PubMed and Sino Med were searched for the relevant articles concerning Wnt signaling pathway and nervous system diseases. The key words were "Wnt signaling pathway, nervous system disease" in English and Chinese, respectively. Finally, 62 pertinent articles were included for result analysis. RESULTS AND CONCLUSION: Wnt signaling pathway is involved in Alzheimer's disease, Parkinson's disease and cerebrovascular disease. However, its role is different in different neurological diseases. For example, the dysfunction of Wnt signaling pathway leads to the disability of neuronal formation, which accelerates the progression of Alzheimer's disease. Besides, Wnt signaling pathway regulates the proliferation of dopaminergic neurons, cell survival and synaptogenesis, thus affecting the development of Parkinson's disease. Therefore, understanding the interaction between ligands, receptors and genes in Wnt signaling pathway in nervous system diseases is conducive to the development of Wnt signaling in the basic research of neurological diseases, and is of great significance for searching for the treatment targets of nervous system diseases.
引文
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[38]Hooper C,Killick R,Lovestone S.The GSK3 hypothesis of Alzheimer's disease.J Neurochem.2008;104(6):1433-1439.
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[40]Maesako M,Uemura K,Kuzuya A,et al.Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling.J Neurochem.2012;121(6):964-973.
[41]Caricasole A,Copani A,Caraci F,et al.Induction of Dickkopf-1,a negative modulator of the Wntpathway,is associated with neuronal degeneration in Alzheimer's brain.J Neurosci.2004;24(26):6021-6027.
[42]Rosi MC,Luccarini I,Grossi C,et al.Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease.JNeurochem.2010;112(6):1539-1551.
[43]Zhou Y,Lou Y,Dai J.Axonal and dendritic changes are associcated with diabetic encephalopathy in rats:an improtanr risk factor for Alzheimer’s disease.J Alzheimers Dis.2013;34(4):937-947.
[44]王薇,张海廷,王淑辉,等.阿尔茨海默病与Wnt信号通路及神经干细胞的关系[J].中国组织工程研究,2013,17(19):3566-3572.
[45]Kojovic M,Higgins A,Jahanshahi M.In Parkinson's disease Stn stimulation enhances responsiveness of movement initiation speed to high reward value.Neuropsychologia.2016;89:273-280.
[46]Okada Y,Murata M,Toda T.Effects of levodopa on vowel articulation in patients with Parkinson's disease.Kobe J Med Sci.2016;61(5):E144-154.
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[48]Wang W,Yang Y,Ying C,et al.Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity.Neuropharmacology.2007;52(8):1678-1684.
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[50]张凯辉,徐宝山,杨强.骨髓间充质干细胞在多种疾病治疗中的应用进展[J].中国组织工程研究,2017,21(21):3400-3406.
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[53]李慧,黄景阳,陈海丽,等.脑缺血再灌注后大鼠海马Wnt7b的表达[J].山东大学学报:医学版,2013,51(2):7-11.
[54]Mastroiacovo F,Busceti CL,Biagioni F,et al.Induction of the Wntantagonist,Dickkopf-1,contributes to the development of neuronal death in models of brain focal ischemia.J Cereb Blood Flow Metab.2009;29(2):264-276.
[55]Shruster A,Ben-Zur T,Melamed E,et al.Wnt Signaling Enhances Neurogenesis and Improves Neurological Function after Focal Ischemic Injury.Plos One.2012;7(7):e40843.
[56]CalióML,Marinho DS,Ko GM,et al.Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress,apoptosis,and hippocampal damage in brain of a spontaneous stroke model.Free Radic Biol Med.2014;70:141-154.
[57]张慧玲,彭会珍,陈素艳,等.Wnt信号通路在缺血性脑卒中后神经发生中的作用研究进展[J].实用医学杂志,2015,31(17):2922-2923.
[58]Aimone JB,Li Y,Lee SW,et al.Regulation and function of adult neurogenesis:from genes to cognition.Physiol Rev.2014;94(4):991-1026.
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[62]张东圆,李明,王正则,等.缺氧诱导因子-1α在缺血性脑卒中模型中介导神经干-祖细胞作用机制的研究进展[J].中国康复理论与实践,2017,23(3):319-322.
[2]Harrisonuy SJ,Pleasure SJ.Wnt signaling and forebrain development.Cold Spring Harb Perspect Biol.2012;4(7):a008094.
[3]Clevers H,Nusse R.Wnt/β-Catenin Signaling and Disease.Cell.2012;149(6):1192-1205.
[4]Mohammed MK,Shao C,Wang J,et al.Wnt/β-catenin signaling playsan ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance.Genes Dis.2016;3(1):11-40.
[5]Rennoll S,Yochum G.Regulation of MYC gene expression by aberrant Wnt/beta-cateninsignaling in colorectal cancer.World J Biol Chem.2015;6(4):290-300.
[6]Bertrand V.β-catenin-driven binary cell fate decisions in animal development.Wiley Interdiscip Rev Dev Biol.2016;5(3):377-88.
[7]曹旻.神经发生中的Wnt信号通路[J].中国组织工程研究,2013,17(2):358-362.
[8]Song X,Xin N,Wang W,et al.Wnt/beta-catenin,an oncogenic pathway targeted by H.pylori ingastric carcinogenesis.Oncotarget.2015;6(34):35579-35588.
[9]文静,王建,罗世兰,等.Wnt/β-catenin信号通路参与脑缺血后神经血管单元调控及相关药物的研究进展[J].中国药理学通报,2016,32(3):310-314.
[10]Prakash S,Swaminathan U.beta catenin in health:A review.J Oral Maxillofac Pathol.2015;19(2):230-238.
[11]FuentesRG,Arai MA,Ishibashi M.Natural compounds with Wntsignal modulating activity.Nat Prod Rep.2015;32(12):1622-1628.
[12]Hohendanner F,Mcculloch AD,Blatter LA,et al.Calcium and IP3dynamics in cardiacmyocytes:experimental and computational perspectives and approaches.Front Pharmacol.2014;5:35.
[13]Endo M,Nishita M,Fujii M,et al.Insight into the role of Wnt5a-induced signaling in normal and cancer cells.Int Rev Cell Mol Biol.2015;314:117-148.
[14]Devenport D.Tissue morphodynamics:Translating planar polarity cues into polarized cell behaviors.Semin Cell Dev Biol.2016;55:99-110.
[15]Carvajal-Gonzalez JM,Mlodzik M.Mechanisms of planar cell polarity establishment in Drosophila.F1000Prime Rep.2014;6:98.
[16]Bielen H,Houart C.The Wntcries many:Wntregulation ofneurogenesis through tissue patterning,proliferation,and asymmetriccell division.Dev Neurobiol.2014;74(8):772-780.
[17]Nouri N,Patel MJ,Joksimovic M,et al.Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis,but results in vacillating dopamine progenitors.Mol Cell Neurosci.2015;68:131-142.
[18]Undi RB,Gutti U,Sahu I,et al.Wnt Signaling:Role in Regulation of Haematopoiesis.Indian J Hematol Blood Transfus.2016;32(2):123-134.
[19]Kielman MF,Rindap M,Gaspar C,et al.Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling.Nature Genetics.2002;33(1):594-605.
[20]Du Y,Zhang S,Yu T,et al.Wnt3a is critical forendothelial progenitor cell-mediated neural stem cell proliferation and differentiation.Mol Med Rep.2016;14(3):2473-2482.
[21]Liu X,Yun F,Shi L,et al.Roles of Signaling Pathways in the Epithelial-Mesenchymal Transition in Cancer.Asian Pac J Cancer Prev.2015;16(15):6201-6206.
[22]Wu J,Saintjeannet JP,Klein PS.Wnt-frizzled signaling in neural crest formation.Trends in Neurosciences.2003;26(26):40-45.
[23]Mayor R,Theveneau E.The role of the non-canonical Wnt-planar cell polarity pathway in neural crest migration.Biochem J.2014;457(1):19-26.
[24]Hall AC,Lucas FR,Salinas PC.Axonal remodeling and synaptic differentiation in the cerebellum is regulated by Wnt-7a signaling.Cell.2000;100(5):525-535.
[25]王建材,冯达云,李洋,等.DKK1对慢性吗啡和纳洛酮处理的培养海马神经元树突棘的影响[J].神经解剖学杂志,2016,32(1):1-6.
[26]Bian WJ,Miao WY,He SJ,et al.A novel Wnt5a-Frizzled4 signaling pathway mediates activity-independent dendrite morphogenesis via the distal PDZ motif of Frizzled 4.Dev Neurobiol.2015;75(8):805-822.
[27]Martin L,Latypova X,Terro F.Post-translational modifications of tau protein:Implications for Alzheimer's disease.Neurochem Int.2011;58(4):458-471.
[28]霍江涛,张小乔,严洁,等.wnt信号传导通路在阿尔茨海默病中的作用[J].中国临床研究,2015,28(6):709-716.
[29]Inestrosa NC,Varela-Nallar L.Wntsignaling in the nervous system and in Alzheimer's disease.J Mol Cell Biol.2014;6(1):64-74.215-227.
[30]姚宏波,廉洁,张善强,等.基于wnt信号通路研究骨髓基质干细胞对阿尔茨海默病的治疗作用[J].世界最新医学信息文摘,2016,16(48):62.
[31]Chacn MA,Varelanallar L,Inestrosa NC.Frizzled-1 is involved in the neuroprotective effect of Wnt3a against Abeta oligomers.J Cell Physiol.2008;217(1):215-227.
[32]Magdesian MH,Carvalho MM,Mendes FA,et al.Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling.J Biol Chem.2008;283(14):9359-9368.
[33]Inestrosa NC,Montecinosoliva C,Fuenzalida M.Wnt Signaling:Role in Alzheimer Disease and Schizophrenia.J Neuroimmune Pharmacol.2012;7(4):788-807.
[34]Li B,Zhong L,Yang X,et al.Wnt5A Signaling Contributes to Abeta-Induced Neuroinflammation and Neurotoxicity.Plos One.2011;6(8):e22920.
[35]De Ferrari GV,Papassotiropoulos A,Biechele T,et al.Common genetic variation within the low-density lipoprotein receptor-related protein 6and late-onset Alzheimer's disease.Proc Natl Acad Sci U S A.2007;104(22):9434-9439.
[36]Folwell J,Cowan CM,Ubhi KK,et al.A beta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease.Exp Neurol.2010;223(2):401-409.
[37]Xu J,Zhang R,Zuo P,et al.Aggravation Effect of Isoflurane on AbetaInduced Apoptosis and Tau Hyperphosphorylation in PC12 Cells.Cell Mol Neurobiol.2012;32(8):1343-1351.
[38]Hooper C,Killick R,Lovestone S.The GSK3 hypothesis of Alzheimer's disease.J Neurochem.2008;104(6):1433-1439.
[39]Kramer T,Schmidt B,Lo MF.Small-Molecule Inhibitors of GSK-3:Structural Insights and Their Application to Alzheimer's Disease Models.Int J Alzheimers Dis.2012;2012:381029.
[40]Maesako M,Uemura K,Kuzuya A,et al.Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling.J Neurochem.2012;121(6):964-973.
[41]Caricasole A,Copani A,Caraci F,et al.Induction of Dickkopf-1,a negative modulator of the Wntpathway,is associated with neuronal degeneration in Alzheimer's brain.J Neurosci.2004;24(26):6021-6027.
[42]Rosi MC,Luccarini I,Grossi C,et al.Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease.JNeurochem.2010;112(6):1539-1551.
[43]Zhou Y,Lou Y,Dai J.Axonal and dendritic changes are associcated with diabetic encephalopathy in rats:an improtanr risk factor for Alzheimer’s disease.J Alzheimers Dis.2013;34(4):937-947.
[44]王薇,张海廷,王淑辉,等.阿尔茨海默病与Wnt信号通路及神经干细胞的关系[J].中国组织工程研究,2013,17(19):3566-3572.
[45]Kojovic M,Higgins A,Jahanshahi M.In Parkinson's disease Stn stimulation enhances responsiveness of movement initiation speed to high reward value.Neuropsychologia.2016;89:273-280.
[46]Okada Y,Murata M,Toda T.Effects of levodopa on vowel articulation in patients with Parkinson's disease.Kobe J Med Sci.2016;61(5):E144-154.
[47]Sancho RM,Law BK.Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wntsignalling pathways.2009;18(20):3955-3968.
[48]Wang W,Yang Y,Ying C,et al.Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity.Neuropharmacology.2007;52(8):1678-1684.
[49]Petitpaitel A,Brau F,Cazareth J,et al.Involvment of cytosolic and mitochondrial GSK-3beta in mitochondrial dysfunction and neuronal cell death of MPTP/MPP-treated neurons.Plos One.2009;4(5):e5491.
[50]张凯辉,徐宝山,杨强.骨髓间充质干细胞在多种疾病治疗中的应用进展[J].中国组织工程研究,2017,21(21):3400-3406.
[51]Kernie SG,Parent JM.Forebrain neurogenesis after focal Ischemic and traumatic brain injury.Neurobiology of Disease.2010;37(37):267-274.
[52]Kreuzberg M,Kanov E,Timofeev O,et al.Increased subventricular zone-derived cortical neurogenesis after ischemic lesion.Experimental Neurology.2010;226(1):90-99.
[53]李慧,黄景阳,陈海丽,等.脑缺血再灌注后大鼠海马Wnt7b的表达[J].山东大学学报:医学版,2013,51(2):7-11.
[54]Mastroiacovo F,Busceti CL,Biagioni F,et al.Induction of the Wntantagonist,Dickkopf-1,contributes to the development of neuronal death in models of brain focal ischemia.J Cereb Blood Flow Metab.2009;29(2):264-276.
[55]Shruster A,Ben-Zur T,Melamed E,et al.Wnt Signaling Enhances Neurogenesis and Improves Neurological Function after Focal Ischemic Injury.Plos One.2012;7(7):e40843.
[56]CalióML,Marinho DS,Ko GM,et al.Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress,apoptosis,and hippocampal damage in brain of a spontaneous stroke model.Free Radic Biol Med.2014;70:141-154.
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