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Astrocyte-specific NDRG2 gene: functions in the brain and neurological diseases

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Abstract

In recent years, the roles of astrocytes of the central nervous system in brain function and neurological disease have drawn increasing attention. As a member of the N-myc downstream-regulated gene (NDRG) family, NDRG2 is principally expressed in astrocytes of the central nervous system. NDRG2, which is involved in cell proliferation and differentiation, is commonly regarded as a tumor suppressor. In astrocytes, NDRG2 affects the regulation of apoptosis, astrogliosis, blood–brain barrier integrity, and glutamate clearance. Several preclinical studies have revealed that NDRG2 is implicated in the pathogenesis of many neurological diseases not limited to tumors (mostly glioma in the nervous system), such as stroke, neurodegeneration (Alzheimer’s disease and Parkinson’s disease), and psychiatric disorders (depression and attention deficit hyperactivity disorder). This review summarizes the biological functions of NDRG2 under physiological and pathological conditions, and further discusses the roles of NDRG2 during the occurrence and development of neurological diseases.

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References

  1. Valori CF, Guidotti G, Brambilla L, Rossi D (2019) Astrocytes: emerging therapeutic targets in neurological disorders. Trends Mol Med. https://doi.org/10.1016/j.molmed.2019.04.010

    Article  PubMed  Google Scholar 

  2. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fasciani I, Pluta P, Gonzalez-Nieto D, Martinez-Montero P, Molano J, Paino CL, Millet O, Barrio LC (2018) Directional coupling of oligodendrocyte connexin-47 and astrocyte connexin-43 gap junctions. Glia 66(11):2340–2352. https://doi.org/10.1002/glia.23471

    Article  PubMed  Google Scholar 

  4. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99(1):21–78. https://doi.org/10.1152/physrev.00050.2017

    Article  CAS  PubMed  Google Scholar 

  5. Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 127(9):3210–3219. https://doi.org/10.1172/JCI90603

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131(3):323–345. https://doi.org/10.1007/s00401-015-1513-1

    Article  CAS  PubMed  Google Scholar 

  7. Flugge G, Araya-Callis C, Garea-Rodriguez E, Stadelmann-Nessler C, Fuchs E (2014) NDRG2 as a marker protein for brain astrocytes. Cell Tissue Res 357(1):31–41. https://doi.org/10.1007/s00441-014-1837-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shimono A, Okuda T, Kondoh H (1999) N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Mech Dev 83(1–2):39–52

    Article  CAS  PubMed  Google Scholar 

  9. Okuda T, Kondoh H (1999) Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc. Biochem Biophys Res Commun 266(1):208–215. https://doi.org/10.1006/bbrc.1999.1780

    Article  CAS  PubMed  Google Scholar 

  10. Deng Y, Yao L, Liu X (2001) Exploring a new gene containing ACP-like domain in human brain and expression of it in E. coli. Prog Biochem Biophys 28(1):5

    Google Scholar 

  11. Zhang J, Li F, Liu X, Shen L, Liu J, Su J, Zhang W, Deng Y, Wang L, Liu N, Han W, Ji S, Yang A, Han H, Yao L (2006) The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with the NDRG2 core promoter. J Biol Chem 281(51):39159–39168. https://doi.org/10.1074/jbc.M605820200

    Article  CAS  PubMed  Google Scholar 

  12. Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F (2002) Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Mol Cell Biochem 229(1–2):35–44

    Article  CAS  PubMed  Google Scholar 

  13. Matschke V, Theiss C, Hollmann M, Schulze-Bahr E, Lang F, Seebohm G, Strutz-Seebohm N (2015) NDRG2 phosphorylation provides negative feedback for SGK1-dependent regulation of a kainate receptor in astrocytes. Front Cell Neurosci 9:387. https://doi.org/10.3389/fncel.2015.00387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Murray JT, Campbell DG, Morrice N, Auld GC, Shpiro N, Marquez R, Peggie M, Bain J, Bloomberg GB, Grahammer F, Lang F, Wulff P, Kuhl D, Cohen P (2004) Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem J 384(Pt 3):477–488. https://doi.org/10.1042/BJ20041057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Burchfield JG, Lennard AJ, Narasimhan S, Hughes WE, Wasinger VC, Corthals GL, Okuda T, Kondoh H, Biden TJ, Schmitz-Peiffer C (2004) Akt mediates insulin-stimulated phosphorylation of Ndrg2: evidence for cross-talk with protein kinase C theta. J Biol Chem 279(18):18623–18632. https://doi.org/10.1074/jbc.M401504200

    Article  CAS  PubMed  Google Scholar 

  16. You MH, Kim BM, Chen CH, Begley MJ, Cantley LC, Lee TH (2017) Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death. Cell Death Differ 24(2):238–250. https://doi.org/10.1038/cdd.2016.114

    Article  CAS  PubMed  Google Scholar 

  17. Tantai J, Pan X, Hu D (2016) RNF4-mediated SUMOylation is essential for NDRG2 suppression of lung adenocarcinoma. Oncotarget 7(18):26837–26843. https://doi.org/10.18632/oncotarget.8663

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hu XY, Liu Z, Zhang KL, Feng J, Liu XF, Wang LY, Wang ZW (2017) SUMO-specific protease 2-mediated deSUMOylation is required for NDRG2 stabilization in gastric cancer cells. Cancer Biomark 21(1):195–201. https://doi.org/10.3233/CBM-170651

    Article  CAS  PubMed  Google Scholar 

  19. Wu GQ, Liu XP, Wang LF, Zhang WH, Zhang J, Li KZ, Dou KF, Zhang XF, Yao LB (2003) Induction of apoptosis of HepG2 cells by NDRG2. Chin J Cell Mol Immunol 19(4):357–360

    CAS  Google Scholar 

  20. Liao H, Wu Z, Huang X, Qiu Z, Wu H (2015) NMyc downstream-regulated gene 2 suppresses proliferation and induces oncosis of OSRC2 human renal cancer cells. Mol Med Rep 11(2):1240–1245. https://doi.org/10.3892/mmr.2014.2882

    Article  CAS  PubMed  Google Scholar 

  21. Yang J, Li Y, Wu L, Zhang Z, Han T, Guo H, Jiang N, Tao K, Ti Z, Liu X, Yao L, Dou K (2010) NDRG2 in rat liver regeneration: role in proliferation and apoptosis. Wound Repair Regener 18(5):524–531. https://doi.org/10.1111/j.1524-475x.2010.00614.x

    Article  Google Scholar 

  22. Li L, Qin X, Shi M, Miao R, Wang L, Liu X, Yao L, Deng Y (2012) Regulation of histone acetylation by NDRG2 in glioma cells. J Neurooncol 106(3):485–492. https://doi.org/10.1007/s11060-011-0700-8

    Article  CAS  PubMed  Google Scholar 

  23. Liu N, Wang L, Li X, Yang Q, Liu X, Zhang J, Wu Y, Ji S, Zhang Y, Yang A, Han H, Yao L (2008) N-Myc downstream-regulated gene 2 is involved in p53-mediated apoptosis. Nucleic Acids Res 36(16):5335–5349. https://doi.org/10.1093/nar/gkn504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cao W, Zhang JL, Feng DY, Liu XW, Li Y, Wang LF, Yao LB, Zhang H, Zhang J (2014) The effect of adenovirus-conjugated NDRG2 on p53-mediated apoptosis of hepatocarcinoma cells through attenuation of nucleotide excision repair capacity. Biomaterials 35(3):993–1003

    Article  CAS  PubMed  Google Scholar 

  25. Li M, Lai X, Zhao Y, Zhang Y, Li M, Li D, Kong J, Zhang Y, Jing P, Li H, Qin H, Shen L, Yao L, Li J, Dou K, Zhang J (2018) Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization. Cell Death Dis 9(2):248. https://doi.org/10.1038/s41419-018-0284-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shen L, Qu X, Ma Y, Zheng J, Chu D, Liu B, Li X, Wang M, Xu C, Liu N, Yao L, Zhang J (2014) Tumor suppressor NDRG2 tips the balance of oncogenic TGF-beta via EMT inhibition in colorectal cancer. Oncogenesis 3:e86. https://doi.org/10.1038/oncsis.2013.48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shen L, Qu X, Li H, Xu C, Wei M, Wang Q, Ru Y, Liu B, Xu Y, Li K, Hu J, Wang L, Ma Y, Li M, Lai X, Gao L, Wu K, Yao L, Zheng J, Zhang J (2018) NDRG2 facilitates colorectal cancer differentiation through the regulation of Skp2-p21/p27 axis. Oncogene 37(13):1759–1774. https://doi.org/10.1038/s41388-017-0118-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shi W, Xu X, Yan F, Wang B, Zhao H, Chan A, Ren Z, Ma Y, Wang F, Yuan J (2017) N-Myc downstream-regulated gene 2 restrains glycolysis and glutaminolysis in clear cell renal cell carcinoma. Oncol Lett 14(6):6881–6887. https://doi.org/10.3892/ol.2017.7024

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ling ZQ, Ge MH, Lu XX, Han J, Wu YC, Liu X, Zhu X, Hong LL (2015) Ndrg2 promoter hypermethylation triggered by helicobacter pylori infection correlates with poor patients survival in human gastric carcinoma. Oncotarget 6(10):8210–8225. https://doi.org/10.18632/oncotarget.3601

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ou XW, Wang RX, Kang MF, Shi JQ (2018) Hypoxia promotes migration and invasion of gastric cancer cells by activating HIF-1alpha and inhibiting NDRG2 associated signaling pathway. Eur Rev Med Pharmacol Sci 22(23):8237–8247. https://doi.org/10.26355/eurrev_201812_16518

    Article  PubMed  Google Scholar 

  31. Kim MJ, Lim J, Yang Y, Lee MS, Lim JS (2014) N-myc downstream-regulated gene 2 (NDRG2) suppresses the epithelial-mesenchymal transition (EMT) in breast cancer cells via STAT3/Snail signaling. Cancer Lett 354(1):33–42. https://doi.org/10.1016/j.canlet.2014.06.023

    Article  CAS  PubMed  Google Scholar 

  32. Wei Y, Yu S, Zhang Y, Zhang Y, Zhao H, Xiao Z, Yao L, Chen S, Zhang J (2017) NDRG2 promotes adriamycin sensitivity through a Bad/p53 complex at the mitochondria in breast cancer. Oncotarget 8(17):29038–29047. https://doi.org/10.18632/oncotarget.16035

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hu W, Yang Y, Fan C, Ma Z, Deng C, Li T, Lv J, Yao W, Gao J (2016) Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers. Apoptosis Int J Progr Cell Death 21(6):675–682. https://doi.org/10.1007/s10495-016-1244-3

    Article  CAS  Google Scholar 

  34. Hwang J, Kim Y, Kang HB, Jaroszewski L, Deacon AM, Lee H, Choi WC, Kim KJ, Kim CH, Kang BS, Lee JO, Oh TK, Kim JW, Wilson IA, Kim MH (2011) Crystal structure of the human N-Myc downstream-regulated gene 2 protein provides insight into its role as a tumor suppressor. J Biol Chem 286(14):12450–12460. https://doi.org/10.1074/jbc.M110.170803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guo Y, Ma J, Wu L, Wang Q, Li X, Zhang Y, Zhang J, Yao L, Liu W (2013) Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1/2 signaling pathway. PLoS ONE 8(4):e61079. https://doi.org/10.1371/journal.pone.0061079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu X, Niu T, Hou W, Zhang J, Yao L (2012) Microarray profiling of HepG2 cells ectopically expressing NDRG2. Gene 503(1):48–55. https://doi.org/10.1016/j.gene.2012.04.044

    Article  CAS  PubMed  Google Scholar 

  37. Kim HS, Kim MJ, Lim J, Yang Y, Lee MS, Lim JS (2014) NDRG2 overexpression enhances glucose deprivation-mediated apoptosis in breast cancer cells via inhibition of the LKB1-AMPK pathway. Genes Cancer 5(5–6):175–185

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pan T, Zhang M, Zhang F, Yan G, Ru Y, Wang Q, Zhang Y, Wei X, Xu X, Shen L, Zhang J, Wu K, Yao L, Li X (2017) NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation. Biochem Biophys Res Commun 483(2):860–866. https://doi.org/10.1016/j.bbrc.2017.01.018

    Article  CAS  PubMed  Google Scholar 

  39. Wang Y, Zhang CY, Xia RH, Han J, Sun B, Sun SY, Li J (2018) The MYB/miR-130a/NDRG2 axis modulates tumor proliferation and metastatic potential in salivary adenoid cystic carcinoma. Cell Death Dis 9(9):917. https://doi.org/10.1038/s41419-018-0966-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ichikawa T, Nakahata S, Fujii M, Iha H, Morishita K (2015) Loss of NDRG2 enhanced activation of the NF-kappaB pathway by PTEN and NIK phosphorylation for ATL and other cancer development. Sci Rep 5:12841. https://doi.org/10.1038/srep12841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tamura T, Ichikawa T, Nakahata S, Kondo Y, Tagawa Y, Yamamoto K, Nagai K, Baba T, Yamaguchi R, Futakuchi M, Yamashita Y, Morishita K (2017) Loss of NDRG2 expression confers oral squamous cell carcinoma with enhanced metastatic potential. Cancer Res 77(9):2363–2374. https://doi.org/10.1158/0008-5472.CAN-16-2114

    Article  CAS  PubMed  Google Scholar 

  42. Kim YJ, Kang HB, Yim HS, Kim JH, Kim JW (2013) NDRG2 positively regulates E-cadherin expression and prolongs overall survival in colon cancer patients. Oncol Rep 30(4):1890–1898. https://doi.org/10.3892/or.2013.2642

    Article  CAS  PubMed  Google Scholar 

  43. Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, Manachai N, Yamakawa N, Hamasaki M, Kitabayashi I, Arai Y, Kanai Y, Taki T, Abe T, Kiyonari H, Shimoda K, Ohshima K, Horii A, Shima H, Taniwaki M, Yamaguchi R, Morishita K (2014) Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun 5:3393. https://doi.org/10.1038/ncomms4393

    Article  CAS  PubMed  Google Scholar 

  44. Jin Z, Gu C, Tian F, Jia Z, Yang J (2017) NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF-beta1/Smad3 pathway. Cell Tissue Res 369(3):603–610. https://doi.org/10.1007/s00441-017-2643-7

    Article  CAS  PubMed  Google Scholar 

  45. Choi SC, Kim KD, Kim JT, Kim JW, Yoon DY, Choe YK, Chang YS, Paik SG, Lim JS (2003) Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells. FEBS Lett 553(3):413–418

    Article  CAS  PubMed  Google Scholar 

  46. Choi SC, Kim KD, Kim JT, Kim JW, Lee HG, Kim JM, Jang YS, Yoon DY, Kim KI, Yang Y, Cho DH, Lim JS (2008) Expression of human NDRG2 by myeloid dendritic cells inhibits down-regulation of activated leukocyte cell adhesion molecule (ALCAM) and contributes to maintenance of T cell stimulatory activity. J Leukoc Biol 83(1):89–98. https://doi.org/10.1189/jlb.0507300

    Article  CAS  PubMed  Google Scholar 

  47. Choi SC, Kim KD, Kim JT, Oh SS, Yoon SY, Song EY, Lee HG, Choe YK, Choi I, Lim JS, Kim JW (2010) NDRG2 is one of novel intrinsic factors for regulation of IL-10 production in human myeloid cell. Biochem Biophys Res Commun 396(3):684–690. https://doi.org/10.1016/j.bbrc.2010.04.162

    Article  CAS  PubMed  Google Scholar 

  48. Lee EB, Kim A, Kang K, Kim H, Lim JS (2010) NDRG2-mediated modulation of SOCS3 and STAT3 activity inhibits IL-10 production. Immune Netw 10(6):219–229. https://doi.org/10.4110/in.2010.10.6.219

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kang K, Jung H, Nam S, Lim JS (2011) NDRG2 Promotes GATA-1 Expression through Regulation of the JAK2/STAT Pathway in PMA-stimulated U937 Cells. Immune Netw 11(6):348–357. https://doi.org/10.4110/in.2011.11.6.348

    Article  PubMed  PubMed Central  Google Scholar 

  50. Foletta VC, Prior MJ, Stupka N, Carey K, Segal DH, Jones S, Swinton C, Martin S, Cameron-Smith D, Walder KR (2009) NDRG2, a novel regulator of myoblast proliferation, is regulated by anabolic and catabolic factors. J Physiol 587(Pt 7):1619–1634. https://doi.org/10.1113/jphysiol.2008.167882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Anderson KJ, Russell AP, Foletta VC (2015) NDRG2 promotes myoblast proliferation and caspase 3/7 activities during differentiation, and attenuates hydrogen peroxide - But not palmitate-induced toxicity. FEBS Open Bio 5:668–681. https://doi.org/10.1016/j.fob.2015.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhu H, Zhao J, Zhou W, Li H, Zhou R, Zhang L, Zhao H, Cao J, Zhu X, Hu H, Ma G, He L, Yao Z, Yao L, Guo X (2012) Ndrg2 regulates vertebral specification in differentiating somites. Dev Biol 369(2):308–318. https://doi.org/10.1016/j.ydbio.2012.07.001

    Article  CAS  PubMed  Google Scholar 

  53. Hou WG, Zhao Y, Shen L, Zhao J, Liu XW, Li Z, Liu XP, Yao LB, Zhang YQ (2009) Differential expression of N-Myc downstream regulated gene 2 (NDRG2) in the rat testis during postnatal development. Cell Tissue Res 337(2):257–267. https://doi.org/10.1007/s00441-009-0814-x

    Article  CAS  PubMed  Google Scholar 

  54. Hou W, Hu J, Li Y, Zhao J, Li Z, Liu X, Yao L, Zhang Y (2010) Altered expression of NDRG2 in the testes of experimental rat model of cryptorchidism. Urology 75(4):985–991. https://doi.org/10.1016/j.urology.2009.05.032

    Article  PubMed  Google Scholar 

  55. Li T, Hu J, He GH, Li Y, Zhu CC, Hou WG, Zhang S, Li W, Zhang JS, Wang Z, Liu XP, Yao LB (1822) Zhang YQ (2012) Up-regulation of NDRG2 through nuclear factor-kappa B is required for Leydig cell apoptosis in both human and murine infertile testes. Biochem Biophys Acta 2:301–313. https://doi.org/10.1016/j.bbadis.2011.11.013

    Article  CAS  Google Scholar 

  56. Nichols NR (2003) Ndrg2, a novel gene regulated by adrenal steroids and antidepressants, is highly expressed in astrocytes. Ann N Y Acad Sci 1007:349–356

    Article  CAS  PubMed  Google Scholar 

  57. Juszczak GR, Stankiewicz AM (2018) Glucocorticoids, genes and brain function. Prog Neuropsychopharmacol Biol Psychiatry 82:136–168. https://doi.org/10.1016/j.pnpbp.2017.11.020

    Article  CAS  PubMed  Google Scholar 

  58. Takahashi K, Saitoh A, Yamada M, Iwai T, Inagaki M (2012) Dexamethasone indirectly induces Ndrg2 expression in rat astrocytes. J Neurosci Res 90(1):160–166. https://doi.org/10.1002/jnr.22727

    Article  CAS  PubMed  Google Scholar 

  59. Zuo ZF, Liao YH, Ding T, Dong YL, Qu J, Wang J, Wei YY, Lu YC, Liu XZ, Li YQ (2015) Astrocytic NDRG2 is involved in glucocorticoid-mediated diabetic mechanical allodynia. Diabetes Res Clin Pract 108(1):128–136. https://doi.org/10.1016/j.diabres.2015.01.023

    Article  CAS  PubMed  Google Scholar 

  60. Ma YL, Qin P, Feng DY, Li Y, Zhang LX, Liu ZY, Yin AQ, Tang WH, Dong HL, Meng LZ, Hou WG, Xiong LZ (2014) Estrogen regulates the expression of Ndrg2 in astrocytes. Brain Res 1569:1–8. https://doi.org/10.1016/j.brainres.2014.04.036

    Article  CAS  PubMed  Google Scholar 

  61. Foletta VC, Brown EL, Cho Y, Snow RJ, Kralli A (1833) Russell AP (2013) Ndrg2 is a PGC-1alpha/ERRalpha target gene that controls protein synthesis and expression of contractile-type genes in C2C12 myotubes. Biochem Biophys Acta 12:3112–3123. https://doi.org/10.1016/j.bbamcr.2013.08.011

    Article  CAS  Google Scholar 

  62. Li Y, Yang J, Li S, Zhang J, Zheng J, Hou W, Zhao H, Guo Y, Liu X, Dou K, Situ Z, Yao L (2011) N-myc downstream-regulated gene 2, a novel estrogen-targeted gene, is involved in the regulation of Na +/K + -ATPase. J Biol Chem 286(37):32289–32299. https://doi.org/10.1074/jbc.M111.247825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li Y, Liu C, Hou W, Li Y, Ma J, Lin K, Situ Z, Xiong L, Li S, Yao L (2014) Retrograde ductal administration of the adenovirus-mediated NDRG2 gene leads to improved sialaden hypofunction in estrogen-deficient rats. Mol Ther J Am Soc Gene Ther 22(5):908–918. https://doi.org/10.1038/mt.2013.286

    Article  CAS  Google Scholar 

  64. Boulkroun S, Fay M, Zennaro MC, Escoubet B, Jaisser F, Blot-Chabaud M, Farman N, Courtois-Coutry N (2002) Characterization of rat NDRG2 (N-Myc downstream regulated gene 2), a novel early mineralocorticoid-specific induced gene. J Biol Chem 277(35):31506–31515. https://doi.org/10.1074/jbc.M200272200

    Article  CAS  PubMed  Google Scholar 

  65. Wielputz MO, Lee IH, Dinudom A, Boulkroun S, Farman N, Cook DI, Korbmacher C, Rauh R (2007) (NDRG2) stimulates amiloride-sensitive Na+ currents in Xenopus laevis oocytes and fisher rat thyroid cells. J Biol Chem 282(38):28264–28273. https://doi.org/10.1074/jbc.M702168200

    Article  CAS  PubMed  Google Scholar 

  66. Boulkroun S, Le Moellic C, Blot-Chabaud M, Farman N, Courtois-Coutry N (2005) Expression of androgen receptor and androgen regulation of NDRG2 in the rat renal collecting duct. Pflugers Arch 451(2):388–394. https://doi.org/10.1007/s00424-005-1410-x

    Article  CAS  PubMed  Google Scholar 

  67. Yang B, Ni YF, Wang WC, Du HY, Zhang H, Zhang L, Zhang WD, Jiang T (2014) Melatonin attenuates intestinal ischemia-reperfusion-induced lung injury in rats by upregulating N-myc downstream-regulated gene 2. J Surg Res. https://doi.org/10.1016/j.jss.2014.11.018

    Article  PubMed  PubMed Central  Google Scholar 

  68. Tao Y, Guo Y, Liu W, Zhang J, Li X, Shen L, Ru Y, Xue Y, Zheng J, Liu X, Yao L (2013) AKT inhibitor suppresses hyperthermia-induced Ndrg2 phosphorylation in gastric cancer cells. Braz J Med Biol Res 46(4):394–404

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wang L, Liu N, Yao L, Li F, Zhang J, Deng Y, Liu J, Ji S, Yang A, Han H, Zhang Y, Han W, Liu X (2008) NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 21(1–3):239–250. https://doi.org/10.1159/000113765

    Article  CAS  Google Scholar 

  70. Liu J, Zhang J, Wang X, Li Y, Chen Y, Li K, Yao L, Guo G (2010) HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res 316(12):1985–1993. https://doi.org/10.1016/j.yexcr.2010.02.028

    Article  CAS  PubMed  Google Scholar 

  71. Alizadeh Zarei M, Takhshid MA, Behzad Behbahani A, Hosseini SY, Okhovat MA, Rafiee Dehbidi GR, Mosleh Shirazi MA (2017) Synergistic effects of NDRG2 overexpression and radiotherapy on cell death of human prostate LNCaP Cells. J Biomed Phys Eng 7(3):257–264

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Langhi C, Pedraz-Cuesta E, Donate Y, Marrero PF, Haro D, Rodriguez JC (2013) Regulation of N-Myc downstream regulated gene 2 by bile acids. Biochem Biophys Res Commun 434(1):102–109. https://doi.org/10.1016/j.bbrc.2013.03.058

    Article  CAS  PubMed  Google Scholar 

  73. Shen L, Zhao ZY, Wang YZ, Ji SP, Liu XP, Liu XW, Che HL, Lin W, Li X, Zhang J, Yao LB (2008) Immunohistochemical detection of Ndrg2 in the mouse nervous system. NeuroReport 19(9):927–931. https://doi.org/10.1097/WNR.0b013e32830163d0

    Article  CAS  PubMed  Google Scholar 

  74. Okuda T, Kokame K, Miyata T (2008) Differential expression patterns of NDRG family proteins in the central nervous system. J Histochem Cytochem Off J Histochem Soc 56(2):175–182. https://doi.org/10.1369/jhc.7A7323.2007

    Article  CAS  Google Scholar 

  75. Takeichi T, Takarada-Iemata M, Hashida K, Sudo H, Okuda T, Kokame K, Hatano T, Takanashi M, Funabe S, Hattori N, Kitamura O, Kitao Y, Hori O (2011) The effect of Ndrg2 expression on astroglial activation. Neurochem Int 59(1):21–27. https://doi.org/10.1016/j.neuint.2011.03.019

    Article  CAS  PubMed  Google Scholar 

  76. Takarada-Iemata M, Kezuka D, Takeichi T, Ikawa M, Hattori T, Kitao Y, Hori O (2014) Deletion of N-myc downstream-regulated gene 2 attenuates reactive astrogliosis and inflammatory response in a mouse model of cortical stab injury. J Neurochem 130(3):374–387. https://doi.org/10.1111/jnc.12729

    Article  CAS  PubMed  Google Scholar 

  77. Mitchelmore C, Buchmann-Moller S, Rask L, West MJ, Troncoso JC, Jensen NA (2004) NDRG2: a novel Alzheimer’s disease associated protein. Neurobiol Dis 16(1):48–58. https://doi.org/10.1016/j.nbd.2004.01.003

    Article  CAS  PubMed  Google Scholar 

  78. Takahashi K, Yamada M, Ohata H, Honda K (2005) Ndrg2 promotes neurite outgrowth of NGF-differentiated PC12 cells. Neurosci Lett 388(3):157–162. https://doi.org/10.1016/j.neulet.2005.06.055

    Article  CAS  PubMed  Google Scholar 

  79. Liu L, Shi M, Wang L, Hou S, Wu Z, Zhao G, Deng Y (2012) Ndrg2 expression in neurogenic germinal zones of embryonic and postnatal mouse brain. J Mol Histol 43(1):27–35. https://doi.org/10.1007/s10735-011-9378-7

    Article  CAS  PubMed  Google Scholar 

  80. Jin PP, Xia F, Ma BF, Li Z, Zhang GF, Deng YC, Tu ZL, Zhang XX, Hou SX (2019) Spatiotemporal expression of NDRG2 in the human fetal brain. Ann Anat 221:148–155. https://doi.org/10.1016/j.aanat.2018.09.010

    Article  PubMed  Google Scholar 

  81. Deng Y, Yao L, Chau L, Ng SS, Peng Y, Liu X, Au WS, Wang J, Li F, Ji S, Han H, Nie X, Li Q, Kung HF, Leung SY, Lin MC (2003) N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int J Cancer 106(3):342–347. https://doi.org/10.1002/ijc.11228

    Article  CAS  PubMed  Google Scholar 

  82. Tepel M, Roerig P, Wolter M, Gutmann DH, Perry A, Reifenberger G, Riemenschneider MJ (2008) Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q112 in primary glioblastoma. Int J Cancer 123(9):2080–2086. https://doi.org/10.1002/ijc.23705

    Article  CAS  PubMed  Google Scholar 

  83. Zhou B, Tang Z, Deng Y, Hou S, Liu N, Lin W, Liu X, Yao L (2014) Tumor suppressor candidate gene, NDRG2 is frequently inactivated in human glioblastoma multiforme. Mol Med Rep 10(2):891–896. https://doi.org/10.3892/mmr.2014.2237

    Article  CAS  PubMed  Google Scholar 

  84. Li L, Wang J, Shen X, Wang L, Li X, Liu Y, Shi M, Zhao G, Deng Y (2011) Expression and prognostic value of NDRG2 in human astrocytomas. J Neurol Sci 308(1–2):77–82. https://doi.org/10.1016/j.jns.2011.06.007

    Article  CAS  PubMed  Google Scholar 

  85. Skiriute D, Steponaitis G, Vaitkiene P, Mikuciunas M, Skauminas K, Tamasauskas A, Kazlauskas A (2014) Glioma malignancy-dependent NDRG2 gene methylation and downregulation correlates with poor patient outcome. J Cancer 5(6):446–456. https://doi.org/10.7150/jca.9140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lusis EA, Watson MA, Chicoine MR, Lyman M, Roerig P, Reifenberger G, Gutmann DH, Perry A (2005) Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 65(16):7121–7126. https://doi.org/10.1158/0008-5472.CAN-05-0043

    Article  CAS  PubMed  Google Scholar 

  87. Skiriute D, Tamasauskas S, Asmoniene V, Saferis V, Skauminas K, Deltuva V, Tamasauskas A (2011) Tumor grade-related NDRG2 gene expression in primary and recurrent intracranial meningiomas. J Neurooncol 102(1):89–94. https://doi.org/10.1007/s11060-010-0291-9

    Article  CAS  PubMed  Google Scholar 

  88. Majchrzak-Celinska A, Paluszczak J, Szalata M, Barciszewska AM, Nowak S, Baer-Dubowska W (2015) DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade. J Cancer Res Clin Oncol 141(9):1593–1601. https://doi.org/10.1007/s00432-015-1930-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu Z, Chopp M (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103–120. https://doi.org/10.1016/j.pneurobio.2015.09.008

    Article  CAS  PubMed  Google Scholar 

  90. Li Y, Shen L, Cai L, Wang Q, Hou W, Wang F, Zeng Y, Zhao G, Yao L, Xiong L (2011) Spatial-temporal expression of NDRG2 in rat brain after focal cerebral ischemia and reperfusion. Brain Res 1382:252–258. https://doi.org/10.1016/j.brainres.2011.01.023

    Article  CAS  PubMed  Google Scholar 

  91. Ma YL, Zhang LX, Liu GL, Fan Y, Peng Y, Hou WG (2017) N-Myc downstream-regulated gene 2 (Ndrg2) is involved in ischemia-hypoxia-induced astrocyte apoptosis: a novel target for stroke therapy. Mol Neurobiol 54(5):3286–3299. https://doi.org/10.1007/s12035-016-9814-5

    Article  CAS  PubMed  Google Scholar 

  92. Li Y, Xu N, Cai L, Gao Z, Shen L, Zhang Q, Hou W, Zhong H, Wang Q, Xiong L (2013) NDRG2 is a novel p53-associated regulator of apoptosis in C6-originated astrocytes exposed to oxygen-glucose deprivation. PLoS ONE 8(2):e57130. https://doi.org/10.1371/journal.pone.0057130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li X, Luo P, Wang F, Yang Q, Li Y, Zhao M, Wang S, Wang Q, Xiong L (2014) Inhibition of N-myc downstream-regulated gene-2 is involved in an astrocyte-specific neuroprotection induced by sevoflurane preconditioning. Anesthesiology 121(3):549–562. https://doi.org/10.1097/ALN.0000000000000314

    Article  CAS  PubMed  Google Scholar 

  94. Wang F, Gao Z, Li X, Li Y, Zhong H, Xu N, Cao F, Wang Q, Xiong L (2013) NDRG2 is involved in anti-apoptosis induced by electroacupuncture pretreatment after focal cerebral ischemia in rats. Neurol Res 35(4):406–414. https://doi.org/10.1179/1743132813Y.0000000159

    Article  CAS  PubMed  Google Scholar 

  95. Wang F, Li M, Li X, Kinden R, Zhou H, Guo F, Wang Q, Xiong L (2016) 2-Arachidonylglycerol protects primary astrocytes exposed to oxygen-glucose deprivation through a blockade of NDRG2 signaling and STAT3 phosphorylation. Rejuvenation Res 19(3):215–222. https://doi.org/10.1089/rej.2015.1703

    Article  CAS  PubMed  Google Scholar 

  96. Takarada-Iemata M, Yoshikawa A, Ta HM, Okitani N, Nishiuchi T, Aida Y, Kamide T, Hattori T, Ishii H, Tamatani T, Le TM, Roboon J, Kitao Y, Matsuyama T, Nakada M, Hori O (2018) N-myc downstream-regulated gene 2 protects blood-brain barrier integrity following cerebral ischemia. Glia 66(7):1432–1446. https://doi.org/10.1002/glia.23315

    Article  PubMed  Google Scholar 

  97. Zhu L, Yu J, Shi Q, Lu W, Liu B, Xu S, Wang L, Han J, Wang X (2011) Strain- and age-related alteration of proteins in the brain of SAMP8 and SAMR1 mice. J Alzheimer’s Dis JAD 23(4):641–654. https://doi.org/10.3233/JAD-2010-101389

    Article  CAS  Google Scholar 

  98. Wang F, Zhong H, Li X, Peng Y, Kinden R, Liang W, Shi M, Liu L, Wang Q, Xiong L (2014) Electroacupuncture attenuates reference memory impairment associated with astrocytic NDRG2 suppression in APP/PS1 transgenic mice. Mol Neurobiol 50(2):305–313. https://doi.org/10.1007/s12035-013-8609-1

    Article  CAS  PubMed  Google Scholar 

  99. Rong XF, Sun YN, Liu DM, Yin HJ, Peng Y, Xu SF, Wang L, Wang XL (2017) The pathological roles of NDRG2 in Alzheimer’s disease, a study using animal models and APPwt-overexpressed cells. CNS Neurosci Ther 23(8):667–679. https://doi.org/10.1111/cns.12716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Herskowitz JH, Seyfried NT, Duong DM, Xia Q, Rees HD, Gearing M, Peng J, Lah JJ, Levey AI (2010) Phosphoproteomic analysis reveals site-specific changes in GFAP and NDRG2 phosphorylation in frontotemporal lobar degeneration. J Proteome Res 9(12):6368–6379. https://doi.org/10.1021/pr100666c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zuo ZF, Wang W, Niu L, Kou ZZ, Zhu C, Zhao XH, Luo DS, Zhang T, Zhang FX, Liu XZ, Wu SX, Li YQ (2011) RU486 (mifepristone) ameliorates cognitive dysfunction and reverses the down-regulation of astrocytic N-myc downstream-regulated gene 2 in streptozotocin-induced type-1 diabetic rats. Neuroscience 190:156–165. https://doi.org/10.1016/j.neuroscience.2011.06.025

    Article  CAS  PubMed  Google Scholar 

  102. Araya-Callis C, Hiemke C, Abumaria N, Flugge G (2012) Chronic psychosocial stress and citalopram modulate the expression of the glial proteins GFAP and NDRG2 in the hippocampus. Psychopharmacology 224(1):209–222. https://doi.org/10.1007/s00213-012-2741-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Takahashi K, Yamada M, Ohata H, Momose K, Higuchi T, Honda K (2005) Expression of Ndrg2 in the rat frontal cortex after antidepressant and electroconvulsive treatment. Int J Neuropsychopharmacol 8(3):381–389. https://doi.org/10.1017/S1461145705005134

    Article  CAS  PubMed  Google Scholar 

  104. Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG (2015) Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 385(9983):2190–2196. https://doi.org/10.1016/S0140-6736(14)61684-6

    Article  PubMed  Google Scholar 

  105. Vegt R, Bertoli-Avella AM, Tulen JH, de Graaf B, Verkerk AJ, Vervoort J, Twigt CM, Maat-Kievit A, van Tuijl R, van der Lijn M, Hengeveld MW, Oostra BA (2010) Genome-wide linkage analysis in a Dutch multigenerational family with attention deficit hyperactivity disorder. Eur J Hum Genet 18(2):206–211. https://doi.org/10.1038/ejhg.2009.148

    Article  CAS  PubMed  Google Scholar 

  106. Li Y, Yin A, Sun X, Zhang M, Zhang J, Wang P, Xie R, Li W, Fan Z, Zhu Y, Wang H, Dong H, Wu S, Xiong L (2017) Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior. J Clin Invest 127(12):4270–4284. https://doi.org/10.1172/JCI94455

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81601149 and 81771322), Military Youth Talent Lifting Project (No. 17-JCJQ-QT-037), Youth Talent Lifting Project of Shaanxi Province (20180305), and Natural Science Foundation of Shaanxi Province (2017JQ8038).

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Li, X., Wu, X., Luo, P. et al. Astrocyte-specific NDRG2 gene: functions in the brain and neurological diseases. Cell. Mol. Life Sci. 77, 2461–2472 (2020). https://doi.org/10.1007/s00018-019-03406-9

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