Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

被引：142

作者：

Wei, Yao ^{[1
]}

Lu, Ming ^{[2
]}

Mei, Meng ^{[1
]}

Wang, Haoran ^{[2
]}

Han, Zhitao ^{[1
]}

Chen, Miaomiao ^{[2
]}

Yao, Hang ^{[2
]}

Song, Nanshan ^{[2
]}

Ding, Xiao ^{[1
]}

Ding, Jianhua ^{[2
]}

Xiao, Ming ^{[2
]}

Hu, Gang ^{[1
,2
,3
]}

机构：

[1] Nanjing Univ Chinese Med, Dept Pharmacol, Nanjing 210023, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Jiangsu Key Lab Neurodegenerat, Nanjing 210029, Jiangsu, Peoples R China

[3] Nanjing Normal Univ, Coll Chem & Mat Sci, Biomed Funct Mat Collaborat Innovat Ctr, Nanjing 210023, Jiangsu, Peoples R China

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

中国国家自然科学基金;

关键词：

PYRUVATE-KINASE M2; SUBSTANTIA-NIGRA; PARKINSONS-DISEASE; STRIATAL ASTROCYTES; GENE-TRANSCRIPTION; CANCER METABOLISM; NEURONS; PKM2; INCREASE; ANTIOXIDANT;

D O I：

10.1038/s41467-020-14788-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.

引用

页数：12

共 65 条

[1]

Alam ZI, 1997, J NEUROCHEM, V69, P1326

[2] Oxidative DNA damage in the parkinsonian brain: An apparent selective increase in 8-hydroxyguanine levels in substantia nigra [J].

Alam, ZI ;

Jenner, A ;

Daniel, SE ;

Lees, AJ ;

Cairns, N ;

Marsden, CD ;

Jenner, P ;

Halliwell, B .

JOURNAL OF NEUROCHEMISTRY, 1997, 69 (03) :1196-1203

[3] ACUTE SENSORY NEUROPATHY-NEURONOPATHY FROM PYRIDOXINE OVERDOSE [J].

ALBIN, RL ;

ALBERS, JW ;

GREENBERG, HS ;

TOWNSEND, JB ;

LYNN, RB ;

BURKE, JM ;

ALESSI, AG .

NEUROLOGY, 1987, 37 (11) :1729-1732

[4] Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis [J].

Anastasiou, Dimitrios ;

Yu, Yimin ;

Israelsen, William J. ;

Jiang, Jian-Kang ;

Boxer, Matthew B. ;

Hong, Bum Soo ;

Tempel, Wolfram ;

Dimov, Svetoslav ;

Shen, Min ;

Jha, Abhishek ;

Yang, Hua ;

Mattaini, Katherine R. ;

Metallo, Christian M. ;

Fiske, Brian P. ;

Courtney, Kevin D. ;

Malstrom, Scott ;

Khan, Tahsin M. ;

Kung, Charles ;

Skoumbourdis, Amanda P. ;

Veith, Henrike ;

Southall, Noel ;

Walsh, Martin J. ;

Brimacombe, Kyle R. ;

Leister, William ;

Lunt, Sophia Y. ;

Johnson, Zachary R. ;

Yen, Katharine E. ;

Kunii, Kaiko ;

Davidson, Shawn M. ;

Christofk, Heather R. ;

Austin, Christopher P. ;

Inglese, James ;

Harris, Marian H. ;

Asara, John M. ;

Stephanopoulos, Gregory ;

Salituro, Francesco G. ;

Jin, Shengfang ;

Dang, Lenny ;

Auld, Douglas S. ;

Park, Hee-Won ;

Cantley, Lewis C. ;

Thomas, Craig J. ;

Heiden, Matthew G. Vander .

NATURE CHEMICAL BIOLOGY, 2012, 8 (10) :839-847

[5] Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses [J].

Anastasiou, Dimitrios ;

Poulogiannis, George ;

Asara, John M. ;

Boxer, Matthew B. ;

Jiang, Jian-kang ;

Shen, Min ;

Bellinger, Gary ;

Sasaki, Atsuo T. ;

Locasale, Jason W. ;

Auld, Douglas S. ;

Thomas, Craig J. ;

Vander Heiden, Matthew G. ;

Cantley, Lewis C. .

SCIENCE, 2011, 334 (6060) :1278-1283

[6]

[Anonymous], 2018, NED TIJDSCHR GENEESK

[7] Parkin function in Parkinson's disease [J].

Arkinson, Connor ;

Walden, Helen .

SCIENCE, 2018, 360 (6386) :267-268

[8] EVIDENCE FOR DOPAMINE D-2 RECEPTOR MESSENGER-RNA EXPRESSION BY STRIATAL ASTROCYTES IN CULTURE - IN-SITU HYBRIDIZATION AND POLYMERASE CHAIN-REACTION STUDIES [J].

BAL, A ;

BACHELOT, T ;

SAVASTA, M ;

MANIER, M ;

VERNA, JM ;

BENABID, AL ;

FEUERSTEIN, C .

MOLECULAR BRAIN RESEARCH, 1994, 23 (03) :204-212

[9]

Bonuccelli Ubaldo, 2007, Expert Rev Neurother, V7, P1391, DOI 10.1586/14737175.7.10.1391

[10] Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease [J].

Burbulla, Lena F. ;

Song, Pingping ;

Mazzulli, Joseph R. ;

Zampese, Enrico ;

Wong, Yvette C. ;

Jeon, Sohee ;

Santos, David P. ;

Blanz, Judith ;

Obermaier, Carolin D. ;

Strojny, Chelsee ;

Savas, Jeffrey N. ;

Kiskinis, Evangelos ;

Zhuang, Xiaoxi ;

Kruger, Rejko ;

Surmeier, D. James ;

Krainc, Dimitri .

SCIENCE, 2017, 357 (6357) :1255-+

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