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Molecular Brain
Published in: Molecular Brain 1/2016

Open Access 01-12-2016 | Research

Glycine confers neuroprotection through microRNA-301a/PTEN signaling

Authors: Juan Chen, Yang Zhuang, Zhi-Feng Zhang, Shu Wang, Ping Jin, Chunjiang He, Peng-Chao Hu, Ze-Fen Wang, Zhi-Qiang Li, Guang-Ming Xia, Gang Li, Yuan Wang, Qi Wan

Published in: Molecular Brain | Issue 1/2016

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Abstract

Background

Glycine is known to protect against neuronal death. However, the underlying mechanism remains to be elucidated. The microRNA-301a is involved in both biological and pathological processes. But it is not known whether microRNA-301a has a neuroprotective property. In this study, we aimed to determine whether glycine-induced neuroprotection requires microRNA-301a-dependent signaling.

Results

We provided the first evidence that glycine increased the expression of microRNA-301a in cultured rat cortical neurons and protected against cortical neuronal death through up-regulation of microRNA-301a after oxygen-glucose deprivation. MicroRNA-301a directly bound the predicted 3′UTR target sites of PTEN and reduced PTEN expression in cortical neurons. We revealed that PTEN down-regulation by microRNA-301a mediated glycine-induced neuroprotective effect following oxygen-glucose deprivation.

Conclusions

Our results suggest that 1) microRNA-301a is neuroprotective in oxygen-glucose deprivation-induced neuronal injury; 2) glycine is an upstream regulator of microRNA-301a; 3) glycine confers neuroprotection through microRNA-301a/PTEN signal pathway.
Literature
1.
Kikuchi G, Motokawa Y, Yoshida T, Hiraga K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84:246–63.CrossRefPubMedPubMedCentral
2.
Tibbetts AS, Appling DR. Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr. 2010;30:57–81.CrossRefPubMed
3.
Gundersen RY, Vaagenes P, Breivik T, Fonnum F, Opstad PK. Glycine--an important neurotransmitter and cytoprotective agent. Acta Anaesthesiol Scand. 2005;49:1108–16.CrossRefPubMed
4.
Betz H, Laube B. Glycine receptors: recent insights into their structural organization and functional diversity. J Neurochem. 2006;97:1600–10.CrossRefPubMed
5.
Bowery NG, Smart TG. GABA and glycine as neurotransmitters: a brief history. Br J Pharmacol. 2006;147 Suppl 1:S109–19.PubMedPubMedCentral
6.
Lynch JW. Native glycine receptor subtypes and their physiological roles. Neuropharmacology. 2009;56:303–9.CrossRefPubMed
7.
Webb TI, Lynch JW. Molecular pharmacology of the glycine receptor chloride channel. Curr Pharm Des. 2007;13:2350–67.CrossRefPubMed
8.
Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51:7–61.PubMed
9.
Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci. 2011;33:1351–65.CrossRefPubMed
10.
Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci Off J Soc Neurosci. 2007;27:2846–57.CrossRef
11.
Yang L, Zhang B, Toku K, Maeda N, Sakanaka M, Tanaka J. Improvement of the viability of cultured rat neurons by the non-essential amino acids L-serine and glycine that upregulates expression of the anti-apoptotic gene product Bcl-w. Neurosci Lett. 2000;295:97–100.CrossRefPubMed
12.
Wheeler MD, Thurman RG. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Am J Phys. 1999;277:L952–9.
13.
Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, et al. L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metab Care. 2003;6:229–40.CrossRefPubMed
14.
Gusev EI, Skvortsova VI, Dambinova SA, Raevskiy KS, Alekseev AA, Bashkatova VG, et al. Neuroprotective effects of glycine for therapy of acute ischaemic stroke. Cerebrovasc Dis. 2000;10:49–60.CrossRefPubMed
15.
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.CrossRefPubMed
16.
Chang N, El-Hayek YH, Gomez E, Wan Q. Phosphatase PTEN in neuronal injury and brain disorders. Trends Neurosci. 2007;30:581–6.CrossRefPubMed
17.
Tamura M, Gu J, Takino T, Yamada KM. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res. 1999;59:442–9.PubMed
18.
Ning K, Pei L, Liao M, Liu B, Zhang Y, Jiang W, et al. Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J Neurosci Off J Soc Neurosci. 2004;24:4052–60.CrossRef
19.
Liu B, Li L, Zhang Q, Chang N, Wang D, Shan Y, et al. Preservation of GABAA receptor function by PTEN inhibition protects against neuronal death in ischemic stroke. Stroke. 2010;41:1018–26.CrossRefPubMed
20.
Zheng M, Liao M, Cui T, Tian H, Fan DS, Wan Q. Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN. J Cell Sci. 2012;125:1556–67.CrossRefPubMedPubMedCentral
21.
Chang N, Li L, Hu R, Shan Y, Liu B, Wang H, et al. Differential regulation of NMDA receptor function by DJ-1 and PINK1. Aging Cell. 2010;9:837–50.CrossRefPubMed
22.
Lee SM, Zhao H, Maier CM, Steinberg GK. The protective effect of early hypothermia on PTEN phosphorylation correlates with free radical inhibition in rat stroke. J Cereb Blood Flow Metab. 2009;29:1589–600.CrossRefPubMedPubMedCentral
23.
Liu C, Wu J, Xu K, Cai F, Gu J, Ma L, et al. Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. J Neurochem. 2010;112:1500–12.CrossRefPubMed
24.
Walker CL, Xu XM. PTEN inhibitor bisperoxovanadium protects oligodendrocytes and myelin and prevents neuronal atrophy in adult rats following cervical hemicontusive spinal cord injury. Neurosci Lett. 2014;573:64–8.CrossRefPubMedPubMedCentral
25.
Goncalves MB, Malmqvist T, Clarke E, Hubens CJ, Grist J, Hobbs C, et al. Neuronal RARbeta Signaling Modulates PTEN Activity Directly in Neurons and via Exosome Transfer in Astrocytes to Prevent Glial Scar Formation and Induce Spinal Cord Regeneration. J Neurosci Off J Soc Neurosci. 2015;35:15731–45.CrossRef
26.
Ohtake Y, Hayat U, Li S. PTEN inhibition and axon regeneration and neural repair. Neural regeneration Res. 2015;10:1363–8.CrossRef
27.
Du K, Zheng S, Zhang Q, Li S, Gao X, Wang J, et al. Pten Deletion Promotes Regrowth of Corticospinal Tract Axons 1 Year after Spinal Cord Injury. J Neurosci Off J Soc Neurosci. 2015;35:9754–63.CrossRef
28.
Geoffroy CG, Lorenzana AO, Kwan JP, Lin K, Ghassemi O, Ma A, et al. Effects of PTEN and Nogo Codeletion on Corticospinal Axon Sprouting and Regeneration in Mice. J Neurosci Off J Soc Neurosci. 2015;35:6413–28.CrossRef
29.
Lewandowski G, Steward O. AAVshRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J Neurosci Off J Soc Neurosci. 2014;34:9951–62.CrossRef
30.
Singh B, Singh V, Krishnan A, Koshy K, Martinez JA, Cheng C, et al. Regeneration of diabetic axons is enhanced by selective knockdown of the PTEN gene. Brain. 2014;137:1051–67.CrossRefPubMedPubMedCentral
31.
Christie KJ, Webber CA, Martinez JA, Singh B, Zochodne DW. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J Neurosci Off J Soc Neurosci. 2010;30:9306–15.CrossRef
32.
Howitt J, Lackovic J, Low LH, Naguib A, Macintyre A, Goh CP, et al. Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. J Cell Biol. 2012;196:29–36.CrossRefPubMedPubMedCentral
33.
Goh CP, Putz U, Howitt J, Low LH, Gunnersen J, Bye N, et al. Nuclear trafficking of Pten after brain injury leads to neuron survival not death. Exp Neurol. 2014;252:37–46.CrossRefPubMed
34.
35.
Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322:963–6.CrossRefPubMedPubMedCentral
36.
Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010;13:1075–81.CrossRefPubMedPubMedCentral
37.
38.
Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005;6:376–85.CrossRefPubMed
39.
Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 2001;15:2654–9.CrossRefPubMedPubMedCentral
40.
41.
42.
Lee YH, Na HS, Jeong SY, Jeong SH, Park HR, Chung J, et al. Comparison of inflammatory microRNA expression in healthy and periodontitis tissues. Biocell. 2011;35:43–9.PubMed
43.
Wang M, Li C, Yu B, Su L, Li J, Ju J, et al. Overexpressed miR-301a promotes cell proliferation and invasion by targeting RUNX3 in gastric cancer. J Gastroenterol. 2013;48:1023–33.CrossRefPubMed
44.
Ma F, Zhang J, Zhong L, Wang L, Liu Y, Wang Y, et al. Upregulated microRNA-301a in breast cancer promotes tumor metastasis by targeting PTEN and activating Wnt/beta-catenin signaling. Gene. 2014;535:191–7.CrossRefPubMed
45.
Xu XD, He XJ, Tao HQ, Zhang W, Wang YY, Ye ZY, et al. Abnormal expression of miR-301a in gastric cancer associated with progression and poor prognosis. J Surg Oncol. 2013;108:197–202.CrossRefPubMed
46.
47.
Dou L, Wang S, Sui X, Meng X, Shen T, Huang X, et al. MiR-301a mediates the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis by regulating PTEN expression. Cell Physiol Biochem. 2015;35:1413–24.CrossRefPubMed
48.
Zhang W, Zhang T, Jin R, Zhao H, Hu J, Feng B, et al. MicroRNA-301a promotes migration and invasion by targeting TGFBR2 in human colorectal cancer. J Exp Clin Cancer Res. 2014;33:113.CrossRefPubMedPubMedCentral
49.
Tanabe M, Nitta A, Ono H. Neuroprotection via strychnine-sensitive glycine receptors during post-ischemic recovery of excitatory synaptic transmission in the hippocampus. J Pharmacol Sci. 2010;113:378–86.CrossRefPubMed
50.
Chen Z, Hu B, Wang F, Du L, Huang B, Li L, et al. Glycine bidirectionally regulates ischemic tolerance via different mechanisms including NR2A-dependent CREB phosphorylation. J Neurochem. 2015;133:397–408.CrossRefPubMed
51.
52.
Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010;467:986–90.CrossRefPubMedPubMedCentral
53.
Zhou P, Jiang W, Wu L, Chang R, Wu K, Wang Z. miR-301a is a candidate oncogene that targets the homeobox gene Gax in human hepatocellular carcinoma. Dig Dis Sci. 2012;57:1171–80.CrossRefPubMed
54.
Kawano M, Tanaka K, Itonaga I, Iwasaki T, Tsumura H. MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing’s sarcoma cells. Int J Oncol. 2016.
55.
Xia X, Zhang K, Cen G, Jiang T, Cao J, Huang K, et al. MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4. Oncotarget. 2015;6:21046–63.CrossRefPubMedPubMedCentral
56.
Panguluri SK, Tur J, Chapalamadugu KC, Katnik C, Cuevas J, Tipparaju SM. MicroRNA-301a mediated regulation of Kv4.2 in diabetes: identification of key modulators. PLoS One. 2013;8:e60545.CrossRefPubMedPubMedCentral
57.
Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, Selmaj KW. MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc Natl Acad Sci U S A. 2012;109:E1248–57.CrossRefPubMedPubMedCentral
58.
Shan Y, Liu B, Li L, Chang N, Li L, Wang H, et al. Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury. J Neurochem. 2009;111:1149–60.CrossRefPubMed
59.
Brewer GJ, Torricelli JR, Evege EK, Price PJ. Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination. J Neurosci Res. 1993;35:567–76.CrossRefPubMed
60.
Haftmann C, Riedel R, Porstner M, Wittmann J, Chang HD, Radbruch A, et al. Direct uptake of Antagomirs and efficient knockdown of miRNA in primary B and T lymphocytes. J Immunol Methods. 2015;426:128–33.CrossRefPubMedPubMedCentral
Metadata
Title
Glycine confers neuroprotection through microRNA-301a/PTEN signaling
Authors
Juan Chen
Yang Zhuang
Zhi-Feng Zhang
Shu Wang
Ping Jin
Chunjiang He
Peng-Chao Hu
Ze-Fen Wang
Zhi-Qiang Li
Guang-Ming Xia
Gang Li
Yuan Wang
Qi Wan
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2016
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/s13041-016-0241-3

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