细胞自噬在帕金森病和阿尔茨海默病中的研究进展

摘要/Abstract

摘要： 细胞自噬是真核生物通过溶酶体途径来降解自身产生的错误折叠蛋白，清除细胞内受损伤或者衰老细胞器的过程，对维持细胞内的稳态以及细胞的代谢生长非常重要。近年来对于细胞自噬的研究发现其与肿瘤、心血管及神经退行性疾病的发生发展均有着密切的关系，细胞自噬的过度或者不足均能够对细胞产生毒性，进而导致错误蛋白的产生，加快疾病的发展进程。因此对细胞自噬的产生、分子机制及其在疾病中作用的研究对这些疾病的预防和控制显得尤为重要。神经退行性疾病多是以错误折叠蛋白和内含体的异常聚集为标志的疾病。这些聚集在神经元或神经组织的异常蛋白能够导致细胞毒性反应或者氧化应激，最终引起神经元的退化或死亡，影响患者的认知或运动等功能。本文主要对细胞自噬发生的机制以及细胞自噬和帕金森病以及阿尔兹海默病之间的关系做一综述。

关键词: 细胞自噬, 神经退行性疾病, 溶酶体, 阿尔兹海默病, 帕金森病

Abstract: Autophagy widely exists in eukaryotic cells and can clear intracellular misfolded protein and damaged or aged organelles through lysosomes pathway. Autophagy is very important for the maintenance of homeostasis and cell metabolism and growth. In recent years，many studies have found that autophagy plays an important role in the development of cancer，cardiovascular and neurodegenerative diseases. Excessive or inadequate autophagy are able to produce toxicity lead to misfolded protein production and accumulation，and accelerate the development of the diseases process. Therefore，the study on the autophagy induction，molecular mechanism and the role of autophagy in the process of diseases prevention and control is very important. The main characteristic of neurodegenerative diseases is the abnormal accumulation of misfolded proteins and inclusion bodies. The misfolded proteins which can cause cellular toxicity or oxidative stress in neurons or nerve tissue can lead to the degeneration or death of neurons. Ultimately，the function of patients’ cognition or movement will be damaged. This review discusses our current understanding of the mechanism of autophagy and the relationship between autophagy and Parkinson’s disease and Alzheimer’s disease.

Key words: autophagy, neurodegenerative diseases, lysosomes, Alzheimer's disease, Parkinson's disease

中图分类号:

R742.5

高杨, 段冷昕. 细胞自噬在帕金森病和阿尔茨海默病中的研究进展[J]. 神经药理学报, 2015, 5(3): 22-27.

GAO Yang, DUAN Leng-xin. Advances of Autophagy in Parkinson’s Disease and Alzheimer’s Disease[J]. ACTA NEUROPHARMACOLOGICA, 2015, 5(3): 22-27.

参考文献

[1] Alfonso Schiavib, Natascia Ventura. The interplay between mitochondria and autophagy and its role in the aging process[J]. Experimental Gerontology, 2014, 56(8): 147-153.

[2] V Nikoletopoulou, M-E Papandreou, N Tavernarakis. Autophagy in the physiology and pathology of the central nervous system[J]. Cell Death Differ, 2015, 22(8):398-407.

[3] Sovan Sarkar. Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers[J]. Biochemical Society Transactions, 2013, 41(5):1103-1130.

[4] Saeid Ghavami, Shahla Shojaei, Behzad Yeganeh, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders[J]. Progress Neurobiology, 2014, 112(12):24-49.

[5] 刘斌，孙静，张晋霞，等. 自噬及自噬相关蛋白在帕金森病模型大鼠黑质纹状体中的表达及意义[J]. 中国神经免疫学和神经病学杂志，2014，21(3)：187-191.

[6] Miki Tsukada, Yoshinori Ohsumi. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae[J]. FEBS Lett, 1993, 33(2):169-174.

[7] Thumm M, Egner R, Koch B M, et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae[J]. FEBS Lett, 1994, 349(2):275-280.

[8] Chang Hwa Jung, Seung-Hyun Ro, Jing Cao, et al. mTOR regulation of autophagy[J]. FEBS Lett, 2010, 584(7):1287-1295.

[9] 曹瑞萍，鲁广秀，张俊士，等. 神经鞘磷脂合成酶2基因敲除小鼠海马神经细胞自噬现象[J]. 解剖学报，2012，43(3)：299-305.

[10] Evangelia Kesidou, Roza Lagoudaki, Olga Touloumi, et al. Autophagy and neurodegenerative disorders[J]. Neural Regeneration Research, 2013, 8(24):2275-2283.

[11] Wang Chen, Zhang Xiong, Teng Zhi-peng, et al. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice[J]. European J Pharmacology, 2014, 740(5):312-320.

[12] Yan-Ning Rui, Wei-dong Le. Selective role of autophagy in neuronal function and neurodegenerative diseases[J]. Neurosci Bull, 2015, 31(4):379-381.

[13] Zhong Yun, Wang Qing-Jun, Li Xian-Ting, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin1-phosphatidylinositol-3-kinase complex[J]. Nat Cell Biol, 2009, 11(4):468-476.

[14] Guiliana Soraya Victoria, Chiara Zurzolo. Trafficking and degradation pathways in pathogenic conversionof prions and prion-like proteins in neurodegenerative diseases[J]. Virus Research, 2015, 207(2):146-154.

[15] 李荣虎，于论，缪珀，等. 缺氧缺血海马组织中自噬相关蛋白Beclin-1和LC3的表达变化以及雷帕霉素对其表达的影响[J]. 中国当代儿科杂志，2015，17(4)：400-404.

[16] Sungwoo Park, Seon-Guk Choi, Seung-Min Yoo, et al. Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy[J]. Autophagy, 2014, 10(11): 1906-1920.

[17] Lei Zhang, Yaru Dong, Xiao-heng Xu, et al. The role of autophagy in Parkinson’s disease[J]. Neural Regeneration Research, 2012, 7(2):141-145.

[18] 张萍，刘康永，蔡增，等. α-突触核蛋白及其在帕金森病发病中的可能机制[J]. 中国临床神经科学，2008，16(5)：556-561.

[19] Nayoung Bae, Sungkwon Chung, Hee Ju Kim, et al. Neuroprotective effect of modified Chungsimyeolda-tang, a traditional Korean herbal formula, via autophagy induction in models of Parkinson's disease[J]. J Ethnopharmacol, 2015, 159(15):93-101.

[20] 陈丽成. 热休克蛋白70在帕金森症患者外周血单核细胞中的表达及意义[J]. 中国现代医学杂志，2014，24(22)：38-42.

[21] Hyun Jung Parka, Jin Young Shina, Ha Na Kima, et al. Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model[J]. Neurobiology Aging, 2014, 35(8):1920-1928.

[22] 张延平，李彦改，徐晓臣，等. 鱼藤酮致帕金森病大鼠黑质中Smac和Bcl-2的表达及意义[J]. 现代肿瘤医学，2015，32(11)：1492-1494.

[23] Priscilla De Rosa, Elettra Sara Marini, Vania Gelmetti, et al. Candidate genes for Parkinson disease: Lessons from pathogenesis[J]. Clinica Chimica Acta, 2015, 449:68-76.

[24] Ashley R Winslow, Chien-Wen Chen, Silvia Corrochano, et al. Rubinsztein α-Synuclein impairs macroautophagy: implications for Parkinson’s disease[J]. J Cell Biology, 2010, 190(6):1023-1037.

[25] 吴锋，秦巨峰. 自噬诱导剂海藻糖对帕金森症小鼠的治疗作用[J]. 交通医学，2014，28(4)：316-317，321.

[26] 丁雪冰，王雪晶，马明明，等. LRRK2活化Rho GTPases信号通路在小胶质细胞吞噬α-突触核蛋白中的作用机制[J]. 中国实用神经疾病杂志，2014，17(23)：17-19.

[27] Marni E Harris-White, Kathie G Ferbas, Ming F Johnson, et al. A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies[J]. Neurobiology of Disease, 2015, 84(11):60-68.

[28] 陈光乐，郑文岭，马文丽. LRRK2基因G2019S 突变帕金森病相关基因的生物信息学分析[J]. 解剖学报，2015，46(3)：304-309.

[29] Sokhna M S Yakhine-Diop, Jose M Bravo-San Pedro, Ruben Gomez-Sanchez R, et al. G2019S LRRK2 mutant fibroblasts from Parkinson's disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy[J]. Toxicology, 2014, 324(3):1-9.

[30] Lin Xian, Loukia Parisiadou, Gu Xing-long, et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant α-synuclein[J]. Neuron, 2009, 64(6): 807-827.

[31] Liu Bin, Sun Jing, Zhang Jin-xia, et al. Autophagy-related protein expression in the substantia nigra and eldepryl intervention in rat models of Parlinson’s disease[J]. Brain Research, 2015, 1625(2):180-188.

[32] 佟明明，姜长安. 帕金森氏病相关蛋白Pink1促进自噬的研究[J]. 四川大学学报: 医学版，2013，44(3)：366-370.

[33] Jenny Jaramillo-Gomez, Andrea Nino, Humberto Arboleda, et al. Overexpression of DJ-1 protects against C2-ceramide-induced neuronal death through activation of the PI3K/AKT pathway and inhibition of autophagy[J]. Neuroscience Letters, 2015, 603(11):71-76.

[34] 王艺璇，喻哲明，丁正同，等. β淀粉样蛋白1-42寡聚体和人重组α-突触核蛋白对原代培养神经元突触的影响[J]. 中国临床神经科学，2014，22(1)：13-19.

[35] 陆蔚天，孙善全，黄娟. Aβ25-35诱导PC12 细胞内Ca2 +浓度升高和自噬发生[J]. 第三军医大学学报，2014，36(4)：355-359.

[36] Rafael Gigli, Gustavo J Pereira, Femanda Antunes, et al. The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy[J]. European J Medicinal Chem, 2016, 107(1):245-254.

[37] Kurt M Lucin, Caitlin E O'Brien, Gregor Bieri, et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease[J]. Neuron, 2013, 79(5):873-886.

[38] Sara Sepe, Roberta Nardacci, Frances Fanelli, et al. Expression of Ambra1 in mouse brain during physiological and Alzheimer type aging[J]. Neurobiol Aging, 2014, 35(1):96-108.

[39] Pilju Youn, Chen Yi-zhe, Darin Y Furgeson. Cytoprotection against beta-amyloid (Aβ) peptide-mediated oxidative damage and autophagy by Keap1 RNAi in human glioma U87mg cells[J]. Neurosci Res, 2015 ,94(4):70-78.

[40] Hung S Y, Huang W P, Liou H C, et al. Autophagy protects neuron from Abeta-induced cytotoxicity[J]. Autophagy, 2009, 5(4):502-510.

[41] 陈雪，孙婧霞，刘源劼，等. β-淀粉样蛋白1-42寡聚体诱导的阿尔茨海默病大鼠海马的Bcl-2表达和caspase-3活性变化[J]. 解剖学杂志，2014，37(2)：181-184.

[42] 强静，马芹颖，顾平，等. 环孢素A对β淀粉样蛋白25-35诱导PC12 细胞损伤的保护作用[J]. 中国老年学杂志，2014，34(13)：3705-3707.

[43] 邹文颖. 自噬调控机制对阿尔兹海默病的影响[J]. 中风与神经疾病杂志，2015，32(7)：658-660.

[44] Preeti J Khandelwal, Alexander M Herman, Hyang-Sook Hoe, et al. Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Aβ in AD models[J]. Human Molecular Genetics, 2012，20(11)：2091-2102.

[45] 贾建新，闫旭升，宋嵬，等. 可溶性Aβ1-42寡聚体双侧海马注射对大鼠认知功能的影响[J]. 包头医学院学报，2015，31(1)：1-2.

[46] Vitor Teixeira, Tania C Medeiros, Rita Vilaça, et al. Ceramide signaling targets the PP2A-like protein phosphatase Sit4p to impair vacuolar function, vesicular trafficking and autophagy in Isc1p deficient cells[J]. Biochim Biophys Acta, 2016, 1861(1):21-33.

[47] 冯利杰，张瑾，丁倩, 等. 自噬参与神经细胞中过表达tau和异常磷酸化tau蛋白的降解[J]. 中国药理学通报，2015，31(3)：356-362.