艾灸“风府”“关元”“足三里”对帕金森病模型大鼠脑黑质Parkin、USP30表达的影响
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摘要
目的观察艾灸"风府""关元""足三里"对帕金森病(PD)模型大鼠脑黑质E3泛素酶Parkin、独特的线粒体去泛素化酶USP30表达的影响,探讨艾灸"风府""关元""足三里"防治PD的作用机制。方法将40只SPF级健康雄性SD大鼠随机分为正常组(8只)、假手术组(8只)、造模组(24只)。造模组采用颈背部皮下注射鱼藤酮造模(1 mg/kg,溶解于二甲基亚砜及0.9%NaCl溶液中),假手术组采用颈背部皮下注射等量不含鱼藤酮的二甲基亚砜及0.9%NaCl溶液混合液。造模40 d后,对各组大鼠进行行为学评分,选择行为学评分高,且分数在2～8分的大鼠14只,然后从正常组、假手术组、造模组分别随机抽取2只大鼠采用免疫组织化学法检测大鼠脑黑质酪氨酸羟化酶(TH)和α-突触核蛋白(α-syn)的表达情况以鉴别造模是否成功。模型鉴定后,造模组(12只)随机分为模型组和艾灸治疗组,每组各6只。艾灸治疗组取穴"风府""关元""足三里",每日相同时间点施灸,1次/d,每穴艾灸15 min;正常组、假手术组和模型组不加干预因素,同艾灸治疗组抓取,穿鼠衣固定。7 d为1个疗程,共治疗2个疗程。艾灸治疗结束后,再次对各组大鼠进行行为学评分。最后,采用免疫蛋白印迹法Western blot检测大鼠脑黑质Parkin、USP30相对表达量。结果免疫组织化学法检测显示模型组和艾灸治疗组较正常组、假手术组TH染色丢失明显,分布不均;模型组和艾灸治疗组较正常组、假手术组α-syn染色丰富而致密。艾灸治疗结束后,艾灸治疗组与模型组比较行为学评分降低(P<0.01);模型组较正常组、假手术组大鼠脑黑质Parkin相对表达量减少(P<0.05)、USP30相对表达量增多(P<0.05);艾灸治疗组较模型组大鼠脑黑质Parkin相对表达量增多(P<0.05)、USP30相对表达量减少(P<0.05)。结论艾灸治疗作用下帕金森病模型大鼠脑黑质Parkin介导的线粒体自噬水平升高,从而降解清除过度表达的USP30,这可能是艾灸治疗帕金森病作用机制之一。
Objective To observe the effects of moxibustion at GV16(Fengfu), CV4(Guanyuan) ST36(Zusanli) on the expression of E3 ubiquitinase Parkin and unique mitochondrial deubiquitinase USP30 in substantia nigra of Parkinson's disease(PD) model rats, and to explore the mechanism of moxibustion atGV16, CV4 and ST36 in preventing and treating PD. Methods Forty healthy male SD rats of SPF grade were randomly divided into normal group(n =8), sham operation group(n =8), and model group(n =24). The rat PD model was made with subcutaneous injection of rotenone(1 mg/kg, dissolved in dimethyl sulfoxide and 0.9% NaCl solution). The sham operation group was made by subcutaneous injection of DMSO and 0.9% NaCl solution without rotenone. Forty days after the establishment of the model, 14 rats with a high score of 2-8 were selected. Then two rats were randomly selected from each group. The expression of tyrosine hydroxylase(TH) and alpha-synuclein(α-syn) in substantia nigra of rats was measured with immunohistochemical method to identify the success of the establishment of the model. After model identification, the model group(n =12) was randomly divided into model group and moxibustion treatment group, 6 in each group. In the moxibustion treatment group, acupoints GV16(Fengfu), CV4(Guanyuan) and ST36(Zusanli) were selected, and moxibustion was applied at the same time once a day, 15 minutes for each acupoint, for 14 consecutive days(7 days is a course of treatment, a total of two courses of treatment). Normal group, sham operation group and model group received no treatment intervention except wearing fixed rat clothes as in with moxibustion group. After moxibustion treatment, the rats in each group were graded for their behavior, and the relative expressions of Parkin and USP30 in substantia nigra of rats were detected by using Western blotting assay. Results Immunohistochemical assay showed that TH staining was significantly lost and unevenly distributed in model group and moxibustion treatment group compared with the normal group and the sham operation group, while the(α-syn) staining was rich and dense in the model group and moxibustion treatment group compared with the normal group and the sham operation group. At the end of moxibustion treatment, the behavioral score of moxibustion treatment group was lower than that of model group(P<0.01); The relative expression of Parkin in substantia nigra of rats in model group decreased(P<0.05) and USP30 increased(P<0.05) compared with normal group and sham operation group; while the relative expression of Parkin in substantia nigra of rats in moxibustion treatment group increased(P<0.05) and USP30 decreased(P<0.05) compared with those in model group. Conclusion Parkin-mediated mitochondrial autophagy in substantia nigra of Parkinson's disease model rats was elevated by moxibustion treatment, thus degrading and clearing over-expressed USP30, which may be one of the mechanisms of moxibustion in the treatment of Parkinson's disease.
Objective To observe the effects of moxibustion at GV16(Fengfu), CV4(Guanyuan) ST36(Zusanli) on the expression of E3 ubiquitinase Parkin and unique mitochondrial deubiquitinase USP30 in substantia nigra of Parkinson's disease(PD) model rats, and to explore the mechanism of moxibustion atGV16, CV4 and ST36 in preventing and treating PD. Methods Forty healthy male SD rats of SPF grade were randomly divided into normal group(n =8), sham operation group(n =8), and model group(n =24). The rat PD model was made with subcutaneous injection of rotenone(1 mg/kg, dissolved in dimethyl sulfoxide and 0.9% NaCl solution). The sham operation group was made by subcutaneous injection of DMSO and 0.9% NaCl solution without rotenone. Forty days after the establishment of the model, 14 rats with a high score of 2-8 were selected. Then two rats were randomly selected from each group. The expression of tyrosine hydroxylase(TH) and alpha-synuclein(α-syn) in substantia nigra of rats was measured with immunohistochemical method to identify the success of the establishment of the model. After model identification, the model group(n =12) was randomly divided into model group and moxibustion treatment group, 6 in each group. In the moxibustion treatment group, acupoints GV16(Fengfu), CV4(Guanyuan) and ST36(Zusanli) were selected, and moxibustion was applied at the same time once a day, 15 minutes for each acupoint, for 14 consecutive days(7 days is a course of treatment, a total of two courses of treatment). Normal group, sham operation group and model group received no treatment intervention except wearing fixed rat clothes as in with moxibustion group. After moxibustion treatment, the rats in each group were graded for their behavior, and the relative expressions of Parkin and USP30 in substantia nigra of rats were detected by using Western blotting assay. Results Immunohistochemical assay showed that TH staining was significantly lost and unevenly distributed in model group and moxibustion treatment group compared with the normal group and the sham operation group, while the(α-syn) staining was rich and dense in the model group and moxibustion treatment group compared with the normal group and the sham operation group. At the end of moxibustion treatment, the behavioral score of moxibustion treatment group was lower than that of model group(P<0.01); The relative expression of Parkin in substantia nigra of rats in model group decreased(P<0.05) and USP30 increased(P<0.05) compared with normal group and sham operation group; while the relative expression of Parkin in substantia nigra of rats in moxibustion treatment group increased(P<0.05) and USP30 decreased(P<0.05) compared with those in model group. Conclusion Parkin-mediated mitochondrial autophagy in substantia nigra of Parkinson's disease model rats was elevated by moxibustion treatment, thus degrading and clearing over-expressed USP30, which may be one of the mechanisms of moxibustion in the treatment of Parkinson's disease.
引文
[1]Jankovic J.Parkinson’s disease:clinical features and diagnosis[J].J Neurol Neurosurg Psychiatry,2008,79(4):368-376.
[2]Tysnes OB,Storstein A.Epidemiology of Parkinson’s disease[J].Journal of Neural Transmission,2017,124(8):901-905.
[3]Lotharius J,Brundin P.Pathogenesis of Parkinson’s disease:dopamine,vesicles and alpha-synuclein[J].Nature Reviews Neuroscience,2002,3(12):932-942.
[4]Spillantini MG,Schmidt ML,Lee VMY,et al.α-Synuclein in Lewy bodies[J].Nature,1997,388(6645):839-840.
[5]Daubner SC,Le T,Wang S.Tyrosine Hydroxylase and Regulation of Dopamine Synthesis[J].Archives of Bio chemistry&Biophysics,2011,508(1):1-12.
[6]Macvicar T.Mitophagy[J].Essays in Biochemistry,2013,55(1):93-104.
[7]Mizushima N,Komatsu M.Autophagy:renovation of cells and tissues[J].Cell,2011,147(4):728-741.
[8]Narendra DP,Jin SM,Tanaka A,et al.PINK1 Is Selec tively Stabilized on Impaired Mitochondria to Activate Parkin[J].Plos Biology,2010,8(1):e1000298.
[9]Matsuda N,Sato S,Shiba K,et al.PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy[J].Autophagy,2010,189(2):211-221.
[10]Skujat D.PINK1/Parkin-mediated mitophagy is depend ent on VDAC1 and p62/SQSTM1[J].Nature Cell Biolo gy,2010,12(2):119-131.
[11]Sarraf SA,Raman M,Guarani-Pereira V,et al.Land scape of the PARKIN-dependent ubiquitylome in re sponse to mitochondrial depolarization[J].Nature,2013,496(7445):372-376.
[12]Narendra D,Tanaka A,Suen DF,et al.Parkin is recruited selectively to impaired mitochondria and promotes their autophagy[J].Journal of Cell Biology,2008,183(5):795-803.
[13]Bingol B,Tea JS,Phu L,et al.The mitochondrial deubiq uitinase USP30 opposes parkin-mediated mitophagy[J].Nature,2014,510(7505):370-375.
[14]张雪淳,蒋丽,伍亚男,等.基于Meta分析的艾灸治疗帕金森病疗效研究[J].亚太传统医药,2016,12(14):96-100.Zhang XC,Jiang L,Wu YN,et al.Moxibustion for Parki son Disorder:A Systematic Review and Meta-analysis[J].Asia-Pacific Traditional Medicine,2016,12(14):96-100.
[15]凃乾,梁艳,马骏,等.电针对帕金森病模型大鼠中脑黑质蛋白酶体的影响[J].中国针灸,2015,35(4):355-360.Tu Q,Liang Y,Ma J,et al.Effects of Electroacupunc ture on proteasome of substantia nigra in rats with Parkinson’s disease[J].Chinese Acupuncture and Moxi bustion,2015,35(4):355-360.
[16]陈忻,张楠,赵晖,等.鱼藤酮致帕金森病大鼠行为学与黑质病理损伤的关系[J].中国神经精神疾病杂志,2008,34(4):232-234.Chen X,Zhang N,Zhao H,et al.The relationship be tween behavior and pathological damage of substantia nigra in rats with Parkinson’s disease induced by rotenone[J].Chinese Journal of Nervous and Mental Dis eases,2008,34(4):232-234.
[17]郭义,方剑乔.实验针灸学实验指导[M〗.北京:中国中医药出版社,2012:46-49.Guo Y,Fang JQ.Experimental Guidance of Experimen tal Acupuncture and Moxibustion[M].Beijing:China Tra ditional Chinese Medicine Press,2012:46-49.
[18]盛慧敏,何建成,王文武,等.帕金森病中医证候的现代文献研究[J].时珍国医国药,2011,22(4):967-969.Sheng HM,He JC,Wang WW,et al.The literature re search of syndromes of TCM about Parkinson’s disease[J].Shizhen Guoyi Guoyao,2011,22(4):967-969.
[19]闫川慧,张俊龙,郭蕾,等.帕金森病中医病机学说探讨[J].中国中医基础医学杂志,2011,17(9):940-941.Yan CH,Zhang JL,Guo L,et al.[J].Discussion on Traditional Chinese Medicine Pathogenesis of Parkin son’s Disease[J].Chinese Journal of Basic Medicine in Traditional Chinese Medicine,2011,17(9):940-941.
[20]魏婕,赵杨,范刚启.针灸治疗帕金森病研究进展[J].辽宁中医药大学学报,2014,16(10):219-221.Wei J,Zhao Y,Fan GQ.Research progress of Acu puncture Treatment in Parkinson’s disease[J].Journal of Liao Ning University of Traditional Chinese Medicine,2014,16(10):219-221.
[21]王文武,何建成.基于肝肾同源理论的帕金森病病因病机及治法研究[J].辽宁中医杂志,2009,36(8):1252-1254.Wang WW,He JC.The Research of Etiology Patho genesis and Treatment by the theory homogeny of liver and kidney for Parkinson’s disease[J].Liaoning Jour nal of Traditional Chinese Medicine,2009,36(8):1252-1254.
[22]李耀.针刺关元穴临床应用验案分析[J].河南中医学院学报,2005,20(5):46-47.Li Y.Ananalysis of Clinical Experience of Puncturing Guanyuan[J].Journal of He Nan University of Chinese Medicine,2005,20(5):46-47.
[23]陈小丽,岳增辉,刘丽,等.足三里穴的古今应用与研究[J].针灸临床杂志,2016,32(7):80-83.Chen XL,Yue ZH,Liu L,et al.Clinical Application and Study of Zusanli(ST36)Acupoint in the Past and Pres ent[J].Journal of Clinical Acupuncture and Moxibus tion,2016,32(7):80-83.
[24]王彬,马骏,王述菊,等.马骏针灸治疗震颤麻痹的经验[J].辽宁中医杂志,2017,44(12):2503-2504.Wang B,Ma J,Wang SJ,et al.Experience of Ma Jun in Treating Parjinson’Disease by Acupuncture and Moxi bustion[J].Liaoning Journal of Traditional Chinese Medicine,2017,44(12):2503-2504.
[25]Alam M,Schmidt WJ.Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats[J].Behavioural Brain Research,2002,136(1):317-324.
[26]Cannon JR,Tapias V,Na HM,et al.A highly reproduci ble rotenone model of Parkinson’s disease[J].Neuro biology of Disease,2009,34(2):279-290.
[27]Betarbet R,Sherer TB,Mackenzie G,et al.Chronic sys temic pesticide exposure reproduces features of Parkinson’s disease[J].Nature Neuroscience,2000,3(12):1301-1306.
[28]Haavik J,Toska K.Tyrosine hydroxylase and Parkinson’s disease[J].Molecular Neurobiology,1998,16(3):285-309.
[29]Kumer SC,Vrana KE.Intricate regulation of tyrosine hydroxylase activity and gene expression[J].Journal of Neurochemistry,2010,67(2):443-462.
[30]Kastner A,Hirsch EC,Agid Y,et al.Tyrosine hydroxy lase protein and messenger RNA in the dopaminergic ni gral neurons of patients with Parkinson’s disease[J].Brain Research,1993,606(2):341-345.
[31]Winslow AR,Chen CW,Corrochano S,et al.α-Synu clein impairs macroautophagy:implications for Parkinson’s disease[J].Journal of Cell Biology,2011,190(6):1023-1037.
[32]Xu J,Kao SY,Lee FJS,et al.Dopamine-dependent neurotoxicity ofα-synuclein:A mechanism for selec tive neurodegeneration in Parkinson disease[J].Nature Medicine,2002,8(6):600-606.
[33]Nakamura N,Hirose S.Regulation of Mitochondrial Morphology by USP30,a Deubiquitinating Enzyme Present in the Mitochondrial Outer Membrane[J].Mo lecular Biology of the Cell,2008,19(5):1903-1911.
[34]Cunningham CN,Baughman JM,Phu L,et al.USP30and parkin homeostatically regulate atypical ubiquitin chains on mitochondria[J].Nature Cell Biology,2015,17(2):160-169.
[35]Sato Y,Okatsu K,Saeki Y,et al.Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30[J].Nature,2017,24(11):911-919.
[36]Gersch M,Gladkova C,Schubert AF,et al.Mechanism and regulation of the Lys6-selective deubiquitinase USP30[J].Nature Structural&Molecular Biology,2017,24(11):920-930.
[37]Yue W,Chen Z,Liu H,et al.A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30[J].Cell Research,2014,24(4):482-496.
[2]Tysnes OB,Storstein A.Epidemiology of Parkinson’s disease[J].Journal of Neural Transmission,2017,124(8):901-905.
[3]Lotharius J,Brundin P.Pathogenesis of Parkinson’s disease:dopamine,vesicles and alpha-synuclein[J].Nature Reviews Neuroscience,2002,3(12):932-942.
[4]Spillantini MG,Schmidt ML,Lee VMY,et al.α-Synuclein in Lewy bodies[J].Nature,1997,388(6645):839-840.
[5]Daubner SC,Le T,Wang S.Tyrosine Hydroxylase and Regulation of Dopamine Synthesis[J].Archives of Bio chemistry&Biophysics,2011,508(1):1-12.
[6]Macvicar T.Mitophagy[J].Essays in Biochemistry,2013,55(1):93-104.
[7]Mizushima N,Komatsu M.Autophagy:renovation of cells and tissues[J].Cell,2011,147(4):728-741.
[8]Narendra DP,Jin SM,Tanaka A,et al.PINK1 Is Selec tively Stabilized on Impaired Mitochondria to Activate Parkin[J].Plos Biology,2010,8(1):e1000298.
[9]Matsuda N,Sato S,Shiba K,et al.PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy[J].Autophagy,2010,189(2):211-221.
[10]Skujat D.PINK1/Parkin-mediated mitophagy is depend ent on VDAC1 and p62/SQSTM1[J].Nature Cell Biolo gy,2010,12(2):119-131.
[11]Sarraf SA,Raman M,Guarani-Pereira V,et al.Land scape of the PARKIN-dependent ubiquitylome in re sponse to mitochondrial depolarization[J].Nature,2013,496(7445):372-376.
[12]Narendra D,Tanaka A,Suen DF,et al.Parkin is recruited selectively to impaired mitochondria and promotes their autophagy[J].Journal of Cell Biology,2008,183(5):795-803.
[13]Bingol B,Tea JS,Phu L,et al.The mitochondrial deubiq uitinase USP30 opposes parkin-mediated mitophagy[J].Nature,2014,510(7505):370-375.
[14]张雪淳,蒋丽,伍亚男,等.基于Meta分析的艾灸治疗帕金森病疗效研究[J].亚太传统医药,2016,12(14):96-100.Zhang XC,Jiang L,Wu YN,et al.Moxibustion for Parki son Disorder:A Systematic Review and Meta-analysis[J].Asia-Pacific Traditional Medicine,2016,12(14):96-100.
[15]凃乾,梁艳,马骏,等.电针对帕金森病模型大鼠中脑黑质蛋白酶体的影响[J].中国针灸,2015,35(4):355-360.Tu Q,Liang Y,Ma J,et al.Effects of Electroacupunc ture on proteasome of substantia nigra in rats with Parkinson’s disease[J].Chinese Acupuncture and Moxi bustion,2015,35(4):355-360.
[16]陈忻,张楠,赵晖,等.鱼藤酮致帕金森病大鼠行为学与黑质病理损伤的关系[J].中国神经精神疾病杂志,2008,34(4):232-234.Chen X,Zhang N,Zhao H,et al.The relationship be tween behavior and pathological damage of substantia nigra in rats with Parkinson’s disease induced by rotenone[J].Chinese Journal of Nervous and Mental Dis eases,2008,34(4):232-234.
[17]郭义,方剑乔.实验针灸学实验指导[M〗.北京:中国中医药出版社,2012:46-49.Guo Y,Fang JQ.Experimental Guidance of Experimen tal Acupuncture and Moxibustion[M].Beijing:China Tra ditional Chinese Medicine Press,2012:46-49.
[18]盛慧敏,何建成,王文武,等.帕金森病中医证候的现代文献研究[J].时珍国医国药,2011,22(4):967-969.Sheng HM,He JC,Wang WW,et al.The literature re search of syndromes of TCM about Parkinson’s disease[J].Shizhen Guoyi Guoyao,2011,22(4):967-969.
[19]闫川慧,张俊龙,郭蕾,等.帕金森病中医病机学说探讨[J].中国中医基础医学杂志,2011,17(9):940-941.Yan CH,Zhang JL,Guo L,et al.[J].Discussion on Traditional Chinese Medicine Pathogenesis of Parkin son’s Disease[J].Chinese Journal of Basic Medicine in Traditional Chinese Medicine,2011,17(9):940-941.
[20]魏婕,赵杨,范刚启.针灸治疗帕金森病研究进展[J].辽宁中医药大学学报,2014,16(10):219-221.Wei J,Zhao Y,Fan GQ.Research progress of Acu puncture Treatment in Parkinson’s disease[J].Journal of Liao Ning University of Traditional Chinese Medicine,2014,16(10):219-221.
[21]王文武,何建成.基于肝肾同源理论的帕金森病病因病机及治法研究[J].辽宁中医杂志,2009,36(8):1252-1254.Wang WW,He JC.The Research of Etiology Patho genesis and Treatment by the theory homogeny of liver and kidney for Parkinson’s disease[J].Liaoning Jour nal of Traditional Chinese Medicine,2009,36(8):1252-1254.
[22]李耀.针刺关元穴临床应用验案分析[J].河南中医学院学报,2005,20(5):46-47.Li Y.Ananalysis of Clinical Experience of Puncturing Guanyuan[J].Journal of He Nan University of Chinese Medicine,2005,20(5):46-47.
[23]陈小丽,岳增辉,刘丽,等.足三里穴的古今应用与研究[J].针灸临床杂志,2016,32(7):80-83.Chen XL,Yue ZH,Liu L,et al.Clinical Application and Study of Zusanli(ST36)Acupoint in the Past and Pres ent[J].Journal of Clinical Acupuncture and Moxibus tion,2016,32(7):80-83.
[24]王彬,马骏,王述菊,等.马骏针灸治疗震颤麻痹的经验[J].辽宁中医杂志,2017,44(12):2503-2504.Wang B,Ma J,Wang SJ,et al.Experience of Ma Jun in Treating Parjinson’Disease by Acupuncture and Moxi bustion[J].Liaoning Journal of Traditional Chinese Medicine,2017,44(12):2503-2504.
[25]Alam M,Schmidt WJ.Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats[J].Behavioural Brain Research,2002,136(1):317-324.
[26]Cannon JR,Tapias V,Na HM,et al.A highly reproduci ble rotenone model of Parkinson’s disease[J].Neuro biology of Disease,2009,34(2):279-290.
[27]Betarbet R,Sherer TB,Mackenzie G,et al.Chronic sys temic pesticide exposure reproduces features of Parkinson’s disease[J].Nature Neuroscience,2000,3(12):1301-1306.
[28]Haavik J,Toska K.Tyrosine hydroxylase and Parkinson’s disease[J].Molecular Neurobiology,1998,16(3):285-309.
[29]Kumer SC,Vrana KE.Intricate regulation of tyrosine hydroxylase activity and gene expression[J].Journal of Neurochemistry,2010,67(2):443-462.
[30]Kastner A,Hirsch EC,Agid Y,et al.Tyrosine hydroxy lase protein and messenger RNA in the dopaminergic ni gral neurons of patients with Parkinson’s disease[J].Brain Research,1993,606(2):341-345.
[31]Winslow AR,Chen CW,Corrochano S,et al.α-Synu clein impairs macroautophagy:implications for Parkinson’s disease[J].Journal of Cell Biology,2011,190(6):1023-1037.
[32]Xu J,Kao SY,Lee FJS,et al.Dopamine-dependent neurotoxicity ofα-synuclein:A mechanism for selec tive neurodegeneration in Parkinson disease[J].Nature Medicine,2002,8(6):600-606.
[33]Nakamura N,Hirose S.Regulation of Mitochondrial Morphology by USP30,a Deubiquitinating Enzyme Present in the Mitochondrial Outer Membrane[J].Mo lecular Biology of the Cell,2008,19(5):1903-1911.
[34]Cunningham CN,Baughman JM,Phu L,et al.USP30and parkin homeostatically regulate atypical ubiquitin chains on mitochondria[J].Nature Cell Biology,2015,17(2):160-169.
[35]Sato Y,Okatsu K,Saeki Y,et al.Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30[J].Nature,2017,24(11):911-919.
[36]Gersch M,Gladkova C,Schubert AF,et al.Mechanism and regulation of the Lys6-selective deubiquitinase USP30[J].Nature Structural&Molecular Biology,2017,24(11):920-930.
[37]Yue W,Chen Z,Liu H,et al.A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30[J].Cell Research,2014,24(4):482-496.