ACMAdvances in Clinical Medicine2161-8712Scientific Research Publishing10.12677/ACM.2018.82027ACM-24374ACM20180200000_75101401.pdf医药卫生 微小RNA对自噬的调控机制及其在帕金森病中的作用 microRNA Regulates Autophagy and Its Role in Parkinson’s Disease 李伟21李舒21青岛大学附属医院神经内科，山东 青岛null150320180802160164© Copyright 2014 by authors and Scientific Research Publishing Inc. 2014This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

微小RNA(microRNA, miRNA)是一类长度约22个核苷酸的内源性非编码RNA，可通过与靶基因mRNA的3’端非编码区(3’UTR)结合实现基因在转录水平后的调控。自噬(Autophagy)是存在于真核细胞中高度保守的、降解受损细胞器和其他大分子物质的一种途径。自噬功能的异常会导致变性蛋白和损伤细胞器的积累，参与帕金森病等神经退行性疾病的发生。有研究表明微小RNA能够通过调节自噬在帕金森病中发挥重要作用。 microRNAs (miRNAs) are endogenous approximately 22 nucleotide non-coding RNAs that post-transcriptionally regulate gene expression via binding to 3’ untranslated regions. Autophagy is a highly conserved pathway for the degradation of damaged organelles and other macromolecular substances in eukaryotic cells. Abnormal autophagy leads to the accumulation of denatured proteins and damaged organelles, and is involved in the development of neurodegenerative dis-eases such as Parkinson’s disease. Studies have shown that microRNAs play an important role in Parkinson’s disease by regulating autophagy.

帕金森病，微小RNA，自噬, Parkinson’s Disease microRNA Autophagy微小RNA对自噬的调控机制及其在帕金森病中的作用<sup> </sup>

李 伟，李 舒

青岛大学附属医院神经内科，山东 青岛

收稿日期：2018年3月18日；录用日期：2018年4月9日；发布日期：2018年4月16日

摘 要

微小RNA(microRNA, miRNA)是一类长度约22个核苷酸的内源性非编码RNA，可通过与靶基因mRNA的3’端非编码区(3’UTR)结合实现基因在转录水平后的调控。自噬(Autophagy)是存在于真核细胞中高度保守的、降解受损细胞器和其他大分子物质的一种途径。自噬功能的异常会导致变性蛋白和损伤细胞器的积累，参与帕金森病等神经退行性疾病的发生。有研究表明微小RNA能够通过调节自噬在帕金森病中发挥重要作用。

关键词 :帕金森病，微小RNA，自噬

Copyright © 2018 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

微小RNA(microRNA，miRNA)是一类长度约22个核苷酸的内源性非编码RNA，可通过识别靶基因mRNA的3’端非编码区(3’UTR)，并与之结合阻止其翻译或mRNA降解来抑制靶基因的表达，并且改变由它们编码的蛋白质的丰度，通过这种方式调节细胞的生长、分化、凋亡、迁移等过程 [1] 。人类发现了大约2000种miRNA，并且它们的数量正在增长。miRNA表达的失调通常与人类疾病相关，在几种神经系统疾病中也报道了miRNA的上调或下调 [2] [3] 。帕金森病 (Parkinson’s disease, PD)是一种常见的以中脑多巴胺能神经元进行性减少以及路易小体(lewy body)的出现为特点的神经退行性疾病，miRNA参与多巴胺能神经元的分化、增殖、凋亡等过成，其在帕金森病患者中的差异表达可以将它们视为有效的帕金森病标志物 [4] 。自噬(Autophagy)是广泛存在于真核细胞中的保守代谢过程，可以降解和回收利用长寿蛋白、蛋白质聚集体、细胞内病原体甚至整个细胞器如线粒体 [5] 。自噬功能的异常会导致变性蛋白和损伤细胞器的积累，这可能是PD等神经退行性疾病发生的重要原因 [6] ，许多研究表明miRNA通过调控自噬相关基因的表达参与自噬的调节 [7] ，因此miRNA、自噬与帕金森病三者之间必然存在密切的联系。本文就帕金森病相关miRNA对自噬的调节及其在帕金森病中的作用进行综述如下。

2. miRNA-181

丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)是细胞信号传递网络中的重要途径之一，p38和c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)是MAPK级联反应的两个重要组分，它们在调控多种细胞活动如增殖、分化、凋亡、自噬等方面发挥重要作用 [8] ，例如JNK通过磷酸化抗凋亡基因Bcl-2破坏Bcl-2与Beclinl复合体，进而促进自噬发生 [9] 。最近Ying [10] 等人发现miRNA-181a的表达在PD模型中明显下调，而miRNA-181a过度表达后则抑制自噬相关蛋白LC3II和Beclin1的表达并降低了细胞凋亡率，此外miRNA-181a参与了p38 MAPK/JNK途径的调节 [11] ，进而Ying等人提出miRNA-181a能够通过调节p38MAPK/JNK途径抑制自噬并减少多巴胺能神经元的凋亡。而在M.Wei [12] 等人的研究提出miRNA-181家族的另一个成员miRNA-181c在帕金森病中发挥保护作用。故miRNA-181作为一个被广泛研究的与帕金森病相关的miRNA，它与帕金森病发病机制的关系还需进一步的证实。

3. miRNA-124

miRNA-124在大脑中高度表达，并且其丰度远高于其他器官组织 [13] ，有研究表明miRNA-124在实验性自身免疫性脑脊髓炎 [14] 、卒中 [15] [16] 等中枢神经系疾病中发挥神经保护作用。此外，另一项研究中发现miRNA-124在1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的PD动物模型中下调 [17] 。而Huiqing [18] 等人的研究更是进一步发现通过上调miRNA-124的表达可以减少MPTP诱导的PD动物模型中多巴胺能神经元的损失。Bim(Bcl-2 interacting mediator of cell death)是Bcl-2家族中BH3-only亚家族的成员，是一种重要的凋亡调节蛋白，同时也是调节多巴胺能神经元凋亡和自噬过程的重要蛋白质 [19] [20] 。Huiqing [18] 等人提出在PD中miRNA-124的神经保护作用机制可能是通过抑制Bim蛋白的表达而减少Bax蛋白易位至线粒体和溶酶体，进而减少细胞自噬和凋亡。

4. miRNA-7和miRNA-153

有研究表明miRNA-7和miRNA-153在神经元中富集，并且都可以调控α-突触核蛋白(α-synuclein，SNCA)的表达 [21] [22] 。SNCA过度表达或突变导致路易小体的出现是PD的典型病理学改变，因此miRNA-7和miRNA-153与PD息息相关。而Apostolia [23] 等人的研究发现miRNA-7和miRNA-153能够通过抑制mTOR(哺乳动物雷帕霉素靶蛋白)信号通路拮抗MPP+诱导的细胞死亡从而保护神经元。mTOR是一种丝/苏氨酸蛋白激酶，属于磷脂酰肌醇3-激酶相关激酶家族，在调控许多通路的信号传导中发挥着重要作用，目前普遍认为mTOR是调节细胞生长、增殖、运动、存活和自噬等上游信号转导通路的汇合点 [24] 。mTOR主要通过两种机制发挥对自噬的调节作用：1) mTOR介导的信号转导作用于下游效应物，如4E-BP1(转录起始因子4E结合蛋白1)、S6K1激酶(核糖体蛋白S6激酶) [25] [26] 控制自噬；2)直接作用于Atg蛋白来调节自噬体的形成 [27] 。因此miRNA-7和miRNA-153对mTOR的抑制作用有可能会引起细胞自噬水平的改变，而自噬本身就在PD中发挥重要作用。但miRNA-7和miRNA-153与自噬的关系及其在PD中发挥的作用仍需进一步研究。

5. miRNA-4487和miRNA-595

ULK1(unc-51 like kinase 1)是一个丝氨酸/苏氨酸激酶，是人类重要的自噬相关基因之一，在自噬中发挥重要作用 [28] ，在自噬过程中，通过饥饿或雷帕霉素抑制mTOR导致ULK1去磷酸化并激活ULK1磷酸化FIP200调节自噬 [29] 。Yi [30] 等人的研究发现在饥饿诱导的SH-SY5Y细胞中miRNA-4487和miRNA-595能够靶向作用于ULK1，并且可以调节ULK1介导的自噬，从而提出ULK1及其目标miRNAs作为未来PD治疗的潜在靶点或生物标志物的可能。在Yi [30] 等人的研究过程中利用计算机模拟分析构建了PD中受ULK1调节的自噬相关激酶网络，并利用基因芯片分析发现了靶向于ULK1的miRNA-4487和miRNA-595，这为我们将miRNA实际应用于PD诊疗过程中提供了新的思路。

6. 其他miRNA

有研究表明在PD患者尸体脑组织中miRNA-34b/c表达下调，并且进一步研究发现如果miRNA-34的表达下降，可能会导致线粒体功能障碍和过氧化损伤 [31] ，另一项研究证明miRNA-494能抑制DJ-1的表达 [32] ，DJ-1是PARK7基因的产物，与PD的发生有关 [33] ，DJ-1的确实会出现蛋白酶体的抑制和活性氧化物的增多 [34] ，而线粒体功能障碍及氧化应激损伤等都与自噬息息相关，它们之间具体的联系仍需进一步研究证明。此外，Alvarez [35] 等人的研究发现分子伴侣介导的自噬通路(chaperone-mediated autophagy，CMA)的自噬调节蛋白LAMP-2和hsc70在PD大脑中含量降低，同时发现在PD患者的黑质致密部组织中靶向LAMP-2(miRNA-21、miRNA-224及miRNA-373)和hsc70(miRNA-26b、miRNA-106a及miRNA-301b)的miRNA含量升高，表明miRNA、自噬及帕金森病存在密切关系。

7. 展望

帕金森病是一种常见的神经退行性疾病，其发病机制非常复杂，而自噬作为存在于真核细胞中的保守代谢过程，广泛参与多种生理和病理过程，同样在帕金森病的发生发展过程中发挥了重要的作用。目前对自噬与帕金森病的相关机制研究尚浅，自噬即可以清除多巴胺神经元内的有害物质，又可因过度自噬对神经元造成损害，自噬的调节通路十分复杂，因此要想将自噬作为治疗帕金森病的切入点，关键是如何更有效、更准确的调控自噬过程。而miRNA的靶向作用机制则为我们精准调控自噬过程提供非常有效的工具。故我们需要尽可能准确而又广泛的发掘miRNA与自噬相关调节通路的联系，阐明其在帕金森病发病过程中起到的作用，随着对miRNA、自噬及帕金森病三者关系研究的不断进展，能够为帕金森病的诊断及个性化治疗提供新的途径。

文章引用

李 伟,李 舒. 微小RNA对自噬的调控机制及其在帕金森病中的作用 microRNA Regulates Autophagy and Its Role in Parkinson’s Disease[J]. 临床医学进展, 2018, 08(02): 160-164. https://doi.org/10.12677/ACM.2018.82027

参考文献ReferencesBader, A.G., Brown, D., Stoudemire, J. and Lammers, P. (2011) Developing Therapeutic microRNAs for Cancer. Gene Therapy, 18, 1121-1126. https://doi.org/10.1038/gt.2011.79Liu, J., Zhang, K.S., Hu, B., Li, S.G., Li, Q., Luo, Y.P., Wang, Y. and Deng, Z.F. (2018) Systematic Analysis of RNA Regulatory Network in Rat Brain after Ischemic Stroke. BioMed Research International, 8354350. https://doi.org/10.1155/2018/8354350Ambrogini, P., Albertini, M.C., Betti, M., Galati, C., Lattanzi, D., et al. (2018) Neurobiological Correlates of Alpha-Tocopherol Antiepileptogenic Effects and MicroRNA Expression Modulation in a Rat Model of Kainate-Induced Seizures. Molecular Neurobiology, 2.Ding, H.X., Huang, Z., Chen, M.J., Wang, C., Chen, X., Chen, J.N., et al. (2016) Identification of a Panel of Five Serum miRNAs as a Biomarker for Parkinson’s Disease. Parkinsonism & Related Disorders, 22, 68-73. https://doi.org/10.1016/j.parkreldis.2015.11.014Mizushima, N. and Komatsu, M. (2011) Autophagy: Ren-ovation of Cells and Tissues. Cell, 147, 728-741. https://doi.org/10.1016/j.cell.2011.10.026Lynch-Day, M.A., Mao, K., Wang, K., Zhao, M. and Klionsky, D.J. (2012) The Role of Autophagy in Parkinson’s Disease. Cold Spring Harbor Perspectives in Medicine, 2, a009357. https://doi.org/10.1101/cshperspect.a009357Gozuacik, D., Akkoc, Y., Ozturk, D.G. and Kocak, M. (2017) Autophagy-Regulating microRNAs and Cancer. Frontiers in Oncology, 7, 65. https://doi.org/10.3389/fonc.2017.00065Gallo, K.A. and Johnson, G.L. (2002) Mixed-Lineage Kinase Control of JNK and p38 MAPK Pathways. Nature Reviews Molecular Cell Biology, 3, 663-672. https://doi.org/10.1038/nrm906Xi, Y.M., Dong, Y.F., Wang, Z.J., Liu, Y., Diao, Z.Z. and Hu, Y.G. (2013) Co-Transfection of Adeno-Associated Virus-Mediated Human Vascular Endothelial Growth Factor(165) and Trans-forming Growth Factor-Beta 1 into Annulus Fibrosus Cells of Rabbit Degenerative Intervertebral Discs. Genetics and Molecular Research, 12, 4895-4908. https://doi.org/10.4238/2013.February.28.11Liu, Y., Song, Y.F. and Zhu, X.T. (2017) MicroRNA-181a Regulates Apoptosis and Autophagy Process in Parkinson’s Disease by Inhibiting p38 Mitogen-Activated Protein Kinase (MAPK)/c-Jun N-Terminal Kinases (JNK) Signaling Pathways. Medical Science Monitor, 23, 1597-1606. https://doi.org/10.12659/MSM.900218Song, M.K., Park, Y.K. and Ryu, J.C. (2013) Polycyclic Aromatic Hydrocarbon (PAH)-Mediated Upregulation of Hepatic microRNA-181 Family Promotes Cancer Cell Migration by Targeting MAPK Phosphatase-5, Regulating the Activation of p38 MAPK. Toxicology and Applied Pharmacology, 273, 130-139. https://doi.org/10.1016/j.taap.2013.08.016Wei, M., Cao, L.J., Zheng, J.L., Xue, L.J., Chen, B., Xiao, F., et al. (2017) MicroRNA-181c Functions as a Protective Factor in a 1-Methyl-4-Phenylpyridinium Iodide-Induced Cellular Parkinson’s Disease Model via BCL2L11. European Review for Medical and Pharmacological Sciences, 21, 3296-3304.Mishima, T., Mizuguchi, Y., Kawahigashi, Y., Takizawa, T. and Takizawa, T. (2007) RT-PCR-Based Analysis of microRNA (miR-1 and -124) Expression in Mouse CNS. Brain Research, 1131, 37-43. https://doi.org/10.1016/j.brainres.2006.11.035Ponomarev, E.D., Veremeyko, T., Barteneva, N., Krichevsky, A.M. and Weiner, H.L. (2011) MicroRNA-124 Promotes Microglia Quiescence and Suppresses EAE by Deactivating Macrophages via the C/EBP-alpha-PU.1 Pathway. Nature Medicine, 17, 64-70. https://doi.org/10.1038/nm.2266Doeppner, T.R., Doehring, M., Bretschneider, E., Zechariah, A., Kaltwasser, B., Muller, B., et al. (2013) MicroRNA-124 Protects against Focal Cerebral Ischemia via Mechanisms Involving Usp14-Dependent REST Degradation. Acta Neuropathologica, 126, 251-265. https://doi.org/10.1007/s00401-013-1142-5Sun, Y., Gui, H., Li, Q., Luo, Z.M., Zheng, M.J., Duan, J.L., et al. (2013) MicroRNA-124 Protects Neurons against Apoptosis in Cerebral Ischemic Stroke. CNS Neuroscience & Therapeutics, 19, 813-819. https://doi.org/10.1111/cns.12142Kanagaraj, N., Beiping, H., Dheen, S.T. and Tay, S.S. (2014) Downregu-lation of miR-124 in MPTP-Treated Mouse Model of Parkinson’s Disease and MPP Iodide-Treated MN9D Cells Mod-ulates the Expression of the Calpain/cdk5 Pathway Proteins. Neuroscience, 272, 167-179. https://doi.org/10.1016/j.neuroscience.2014.04.039Wang, H., Ye, Y., Zhu, Z., Mo, L., Lin, C., Wang, Q., et al. (2016) MiR-124 Regulates Apoptosis and Autophagy Process in MPTP Model of Parkinson’s Disease by Targeting to Bim. Brain Pathology, 26, 167-176. https://doi.org/10.1111/bpa.12267Bove, J., Martinez-Vicente, M., Dehay, B., Perier, C., Recasens, A., Bombrun, A., et al. (2014) BAX Channel Activity Mediates Lysosomal Disruption Linked to Parkinson Disease. Au-tophagy, 10, 889-900. https://doi.org/10.4161/auto.28286Perier, C., Bove, J., Wu, D.C., Dehay, B., Choi, D.K., Jackson-Lewis, V., et al. (2007) Two Molecular Pathways initiate Mitochondria-Dependent Dopaminergic Neurodegeneration in Experimental Parkinson’s Disease. Proceedings of the National Academy of Sciences of the United States of America, 104, 8161-8166. https://doi.org/10.1073/pnas.0609874104Doxakis, E. (2010) Post-Transcriptional Regulation of Alpha-Synuclein Expression by mir-7 and mir-153. The Journal of Biological Chemistry, 285, 12726-12734. https://doi.org/10.1074/jbc.M109.086827Junn, E., Lee, K.W., Jeong, B.S., Chan, T.W., Im, J.Y. and Mouradian, M.M. (2009) Repression of Alpha-Synuclein Expression and Toxicity by microRNA-7. Proceedings of the National Academy of Sciences of the United States of America, 106, 13052-13057. https://doi.org/10.1073/pnas.0906277106Fragkouli, A. and Doxakis, E. (2014) miR-7 and miR-153 Protect Neurons against MPP(+)-Induced Cell Death via Upregulation of mTOR Pathway. Frontiers in Cellular Neuroscience, 8, 182. https://doi.org/10.3389/fncel.2014.00182Klionsky, D.J., Abdalla, F.C., Abeliovich, H., Abraham, R.T., Acevedo-Arozena, A., Adeli, K., et al. (2012) Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. Autophagy, 8, 445-544. https://doi.org/10.4161/auto.19496Rosenfeldt, M.T. and Ryan, K.M. (2009) The Role of Autophagy in Tumour Development and Cancer Therapy. Expert Reviews in Molecular Medicine, 11, e36. https://doi.org/10.1017/S1462399409001306Scott, R.C., Schuldiner, O. and Neufeld, T.P. (2004) Role and Regulation of Starvation-Induced Autophagy in the Drosophila Fat Body. Developmental Cell, 7, 167-178. https://doi.org/10.1016/j.devcel.2004.07.009Rubinsztein, D.C. (2010) Autophagy: Where Next? EMBO Reports, 11, 3. https://doi.org/10.1038/embor.2009.253Lee, E.J. and Tournier, C. (2011) The Requirement of Uncoordinated 51-Like Kinase 1 (ULK1) and ULK2 in the Regulation of Autophagy. Autophagy, 7, 689-695. https://doi.org/10.4161/auto.7.7.15450Jung, C.H., Jun, C.B., Ro, S.H., Kim, Y.M., Otto, N.M., Cao, J., et al. (2009) ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery. Molecular Biology of the Cell, 20, 1992-2003. https://doi.org/10.1091/mbc.E08-12-1249Chen, Y., Wang, S.Y., Zhang, L., Xie, T., Song, S.C., Huang, J., et al. (2015) Identification of ULK1 as a Novel Biomarker Involved in miR-4487 and miR-595 Regulation in Neuroblastoma SH-SY5Y Cell Autophagy. Scientific Reports, 5, Article No. 11035.Minones-Moyano, E., Porta, S., Escaramis, G., Rabionet, R., Iraola, S., Kagerbauer, B., et al. (2011) MicroRNA Profiling of Parkinson’s Disease Brains Identifies Early Downregulation of miR-34b/c Which Modulate Mitochondrial Function. Human Molecular Genetics, 20, 3067-3078. https://doi.org/10.1093/hmg/ddr210Xiong, R., Wang, Z., Zhao, Z., Li, H., Chen, W., Zhang, B., et al. (2014) MicroRNA-494 Reduces DJ-1 Expression and Exacerbates Neurodegeneration. Neurobiology of Aging, 35, 705-714. https://doi.org/10.1016/j.neurobiolaging.2013.09.027Scholz, S.W., Mhyre, T., Ressom, H., Shah, S. and Federoff, H.J. 2012 (2012) Genomics and Bioinformatics of Parkinson’s Disease. Cold Spring Harbor Perspectives in Medicine, 2, a009449. https://doi.org/10.1101/cshperspect.a009449Shendelman, S., Jonason, A., Martinat, C., Leete, T. and Abeliovich, A. (2004) DJ-1 Is a Redox-Dependent Molecular Chaperone That Inhibits Alpha-Synuclein Aggregate Formation. PLOS Biology, 2, 1764-1773. https://doi.org/10.1371/journal.pbio.0020362Alvarez-Erviti, L., Seow, Y., Schapira, A.H.V., Rodriguez-Oroz, M.C., Obeso, J.A. and Cooper, J.M. (2013) Influence of microRNA Deregulation on Chaperone-Mediated Autophagy and Alpha-Synuclein Pathology in Parkinson’s Disease. Cell Death & Disease, 4, e545.