Tetramethylpyrazine analogue T-006 promotes clearance of alpha-synuclein by enhancing proteasome activity in Parkinson disease models  

作　　者：ZHOU He-feng SHAO Min GUO Bao-jian LI Chu-wen LU Yu-cong YANG Xuan-jun LI Sheng-nan LI Hai-tao ZHU Qi ZHONG Han-bing WANG Yu-qiang ZHANG Zai-jun LU Jia-hong LEE Ming-yuen Simon 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences,University of Macao,Macao 999078,China [2]Department of Bioengineering,Zhuhai Campus of Zunyi Medical College,Zhuhai 519041,China [3]Institute of New Drug Research,College of Pharmacy,Jinan University,Guangzhou 510000,China [4]Department of Biology,South University of Science and Technology,Shenzhen 518000,China

出　　处：《中国药理学与毒理学杂志》2019年第9期658-659,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：Science and Technology Development Fund(FDCT)of Macao SAR(069/2015/A2;134/2014/A3;062-2017-AIR);Research Committee,University of Macao(MYRG2015-00182-ICMS-QRCM;MYRG2015-00214-ICMSQRCM;MYRG139(Y1-L4)-ICMS12-LMY;and MYRG2016-00129-ICMS-QRCM)

摘　　要：OBJECTIVE To investigate the effects of T-006(tetramethylpyrazine derivative)in promotingα-Synuclein(α-Syn)degradation and evaluated the neuroprotective effects in cellular and animalα-Syn model of Parkinson disease(PD).METHODS The inducible PC12 cells overexpressingα-syn and the homozygous transgenic(Tg)mice expressing A53T humanα-syn were used to evaluate the neuroprotective effects of T-006.For cellular study,MTT,Western blotting,proteasomal activity assay and qRT-PCR were applied to analyze the pharmacological effects and underlying mecha⁃nisms.The gene knock-down and overexpression approaches were used to dissect the molecular signaling pathways.For animal study,ten-month-old homozygousα-Syn Tg mice were treated with T-006(3 mg·kg-1)daily by gavage for four weeks.The Western blotting,immunohistochemistry and behavioral tests were applied to determine the neuropatho⁃logical changes.RESULTS T-006 promoted the degradation of WT and mutantα-Syn in PC12α-Syn inducible cells via an ubiquitin-proteasome system(UPS)dependent and autophagy-lysosome pathway independent manner.The mecha⁃nism of action involved the upregulation of 20S proteasome subunit LMP7 expression,which leads to activation of the chymotrypsin-like proteasomal activity for protein degradation.Mechanistically,we demonstrated that T-006 activated PKA/Akt/mTOR pathway upstream for LMP 7 up-regulation and UPS activation.Finally,we illustrated that T-006 promoted both Triton-soluble and-insoluble forms ofα-syn and protected againstα-Syn-induced neurotoxicity in A53Tα-Syn Tg mice.CONCLUSION T-006 is a potent UPS activator which promotes the degradation of pathogenic proteinα-Syn in cellular and animal PD models.Our study thus high-lights the therapeutic potential of small molecular UPS activator like T-006 in the treatment of PD and related conditions.OBJECTIVE To investigate the effects of T-006（tetramethylpyrazine derivative） in promoting α-Synuclein（α-Syn） degradation and evaluated the neuroprotective effects in cellular and animal α-Syn model of Parkinson disease（PD）. METHODS The inducible PC12 cells overexpressing α-syn and the homozygous transgenic（Tg） mice expressing A53 T human α-syn were used to evaluate the neuroprotective effects of T-006. For cellular study, MTT, Western blotting,proteasomal activity assay and q RT-PCR were applied to analyze the pharmacological effects and underlying mechanisms. The gene knock-down and overexpression approaches were used to dissect the molecular signaling pathways.For animal study, ten-month-old homozygous α-Syn Tg mice were treated with T-006(3 mg·kg-1) daily by gavage for four weeks. The Western blotting, immunohistochemistry and behavioral tests were applied to determine the neuropathological changes. RESULTS T-006 promoted the degradation of WT and mutant α-Syn in PC12 α-Syn inducible cells via an ubiquitin-proteasome system（UPS） dependent and autophagy-lysosome pathway independent manner. The mechanism of action involved the upregulation of 20 S proteasome subunit LMP7 expression, which leads to activation of the chymotrypsin-like proteasomal activity for protein degradation. Mechanistically, we demonstrated that T-006 activated PKA/Akt/mT OR pathway upstream for LMP 7 up-regulation and UPS activation. Finally, we illustrated that T-006 promoted both Triton-soluble and-insoluble forms of α-syn and protected against α-Syn-induced neurotoxicity in A53 T α-Syn Tg mice. CONCLUSION T-006 is a potent UPS activator which promotes the degradation of pathogenic protein α-Syn in cellular and animal PD models. Our study thus high-lights the therapeutic potential of small molecular UPS activator like T-006 in the treatment of PD and related conditions.

关 键 词：Α-SYNUCLEIN degradation LMP7 proteasome activity Parkinson disease 

分 类 号：R73[医药卫生—肿瘤]