c-Jun N-terminal kinase 3 deficiency protects axotomized retinal ganglion cells via affecting mitochondria involved apoptosis pathway
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摘要
AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma. METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells(RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction(PCR) and Western blotting assay. RESULTS: We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomyinduced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1(TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION: It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.
AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma.METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells(RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction(PCR) and Western blotting assay. RESULTS: We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomyinduced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1(TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION: It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.
AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma.METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells(RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction(PCR) and Western blotting assay. RESULTS: We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomyinduced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1(TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION: It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.
引文
1 Guo XX,An S,Yang Y,Liu Y,Hao Q,Tang T,Xu TR.Emerging role of the Jun N-terminal kinase interactome in human health.Cell Biol Int2018;42(7):756-768.
2 Gupta S,Barrett T,Whitmarsh AJ,Cavanagh J,Sluss HK,Dérijard B,Davis RJ.Selective interaction of JNK protein kinase isoforms with transcription factors.EMBO J 1996;15(11):2760-2770.
3 Ploia C,Antoniou X,Sclip A,Grande V,Cardinetti D,Colombo A,Canu N,Benussi L,Ghidoni R,Forloni G,Borsello T.JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models.J Alzheimer Dis2011;26(2):315-329.
4 Auladell C,de Lemos L,Verdaguer E,Ettcheto M,Busquets O,Lazarowski A,Beas-Zarate C,Olloquequi J,Folch J,Camins A.Role of JNK isoforms in the kainic acid experimental model of epilepsy and neurodegeneration.Front Biosci 2017;22:795-814.
5 Kumar A,Singh UK,Kini SG,Garg V,Agrawal S,Tomar PK,Pathak P,Chaudhary A,Gupta P,Malik A.JNK pathway signaling:a novel and smarter therapeutic targets for various biological diseases.Future Med Chem 2015;7(15):2065-2086.
6 Waetzig V,Zhao Y,Herdegen T.The bright side of JNKs:multitalented mediators in neuronal sprouting,brain development and nerve fiber regeneration.Prog Neurobiol 2006;80(2):84-97.
7 Yang G,Liu Y,Yang K,Liu R,Zhu S,Coquinco A,Wen W,Kojic L,Jia W,Cynader M.Isoform-specific palmitoylation of JNK regulates axonal development.Cell Death Differ 2012;19(4):553-561.
8 Yao W,Frie M,Pan J,Pak K,Webster N,Wasserman SI,Ryan AF.C-Jun N-terminal kinase(JNK)isoforms play differing roles in otitis media.BMC Immunol 2014;15:46.
9 Liu C,Zhang CW,Zhou Y,et al.APP upregulation contributes to retinal ganglion cell degeneration via JNK3.Cell Death Differ 2018;25(4):661-676.
10 Grynberg K,Ma FY,Nikolic-Paterson DJ.The JNK signaling pathway in renal fibrosis.Front Phsiol 2017;8:829.
11 Borsello T,Forloni G.JNK signalling:a possible target to prevent neurodegeneration.Curr Pharm Des 2007;13(18):1875-1886.
12 Sabapathy K.Role of the JNK pathway in human diseases.Prog Mol Biol Transl Sci 2012;106:145-169.
13 Pal M,Febbraio MA,Lancaster GI.The roles of C-Jun NH2-terminal kinases(JNKs)in obesity and insulin resistance.J Physiol(Lond)2016;594(2):267-279.
14 Watanabe M,Fukuda Y.Survival and axonal regeneration of retinal ganglion cells in adult cats.Prog Retin Eye Res 2002;21(6):529-553.
15 Almasieh M,Catrinescu MM,Binan L,Costantino S,Levin LA.Axonal degeneration in retinal ganglion cells is associated with a membrane polarity-sensitive redox process.J Neurosci 2017;37(14):3824-3839.
16 Haase G,Pettmann B,Raoul C,Henderson CE.Signaling by death receptors in the nervous system.Curr Opin Neurobiol 2008;18(3):284-291.
17 Selim LA,Hassaan H.Mitochondrial diseases as model of neurodegeneration.Adv Exp Med Biol 2017;1007:129-155.
18 Sessler T,Healy S,Samali A,Szegezdi E.Structural determinants of DISC function:new insights into death receptor-mediated apoptosis signalling.Pharmacol Ther 2013;140:186-199.
19 Gupta R,Ghosh S.Putative roles of mitochondrial voltage-dependent anion channel,Bcl-2 family proteins and c-Jun N-terminal kinases in ischemic stroke associated apoptosis.Biochim Open 2017;4:47-55.
20 Zhang XL,Zhang CX,Wang N,Li Y,Zhang DB,Li Q.MicroRNA-486alleviates hypoxia-induced damage in H9C2 cells by targeting NDRG2to inactivate JNK/C-Jun and NF-κB signaling pathways.Cell Physiol Biochem 2018;48(6):2483-2492.
21 Chang KW,Zong HF,Ma KG,Zhai WY,Yang WN,Hu XD,Xu JH,Chen XL,Ji SF,Qian YH.Activation ofα7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways.Neurochem Int 2018;120:238-250.
22 Chen K,Lu YW,Liu CY,Zhang LM,Fang ZY,Yu GR.Morroniside prevents H2O2 or Aβ1-42-induced apoptosis via attenuating JNK and p38MAPK phosphorylation.Eur J Pharmacol 2018;834:295-304.
23 Dhanasekaran DN,Reddy EP.JNK-signaling:a multiplexing hub in programmed cell death.Genes Cancer 2017;8:682-694.
24 Brecht S,Kirchhof R,Chromik A,et al.Specific pathophysiological functions of JNK isoforms in the brain.Eur J Neurosci 2005;21(2):363-377.
25 Keramaris E,Ruzhynsky VA,Callaghan SM,Wong E,Davis RJ,Flavell R,Slack RS,Park DS.Required roles of Bax and JNKs in central and peripheral nervous system death of retinoblastoma-deficient mice.JBiol Chem 2008;283(1):405-415.
26 Crocker SJ,Hayley SP,Smith PD,Mount MP,Lamba WR,Callaghan SM,Slack RS,Park DS.Regulation of axotomy-induced dopaminergic neuron death and c-jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase.J Neurochem 2006;96(2):489-499.
27 Wen XR,Fu YY,Liu HZ,et al.Neuroprotection of sevoflurane against ischemia/reperfusion-induced brain injury through inhibiting JNK3/caspase-3 by enhancing akt signaling pathway.Mol Neurobiol2016;53:1661-1671.
28 Ambacher KK,Pitzul KB,Karajgikar M,Hamilton A,Ferguson SS,Cregan SP.The JNK-and AKT/GSK3β-signaling pathways converge to regulate puma induction and neuronal apoptosis induced by trophic factor deprivation.PLo S One 2012;7(10):e46885.
29 Zheng J,Qi JG,Zou Q,Zhang ZZ.Construction of PLGA/JNK3-shRNA nanoparticles and their protective role in hippocampal neuron apoptosis induced by oxygen and glucose deprivation.RSC Adc2018;8(36):20108-20116.
30 Maino B,Paparone S,Severini C,Ciotti MT,D’agata V,Calissano P,Cavallaro S.Drug target identification at the crossroad of neuronal apoptosis and survival.Expert Opin Drug Discov 2017;12(3):249-259.
2 Gupta S,Barrett T,Whitmarsh AJ,Cavanagh J,Sluss HK,Dérijard B,Davis RJ.Selective interaction of JNK protein kinase isoforms with transcription factors.EMBO J 1996;15(11):2760-2770.
3 Ploia C,Antoniou X,Sclip A,Grande V,Cardinetti D,Colombo A,Canu N,Benussi L,Ghidoni R,Forloni G,Borsello T.JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models.J Alzheimer Dis2011;26(2):315-329.
4 Auladell C,de Lemos L,Verdaguer E,Ettcheto M,Busquets O,Lazarowski A,Beas-Zarate C,Olloquequi J,Folch J,Camins A.Role of JNK isoforms in the kainic acid experimental model of epilepsy and neurodegeneration.Front Biosci 2017;22:795-814.
5 Kumar A,Singh UK,Kini SG,Garg V,Agrawal S,Tomar PK,Pathak P,Chaudhary A,Gupta P,Malik A.JNK pathway signaling:a novel and smarter therapeutic targets for various biological diseases.Future Med Chem 2015;7(15):2065-2086.
6 Waetzig V,Zhao Y,Herdegen T.The bright side of JNKs:multitalented mediators in neuronal sprouting,brain development and nerve fiber regeneration.Prog Neurobiol 2006;80(2):84-97.
7 Yang G,Liu Y,Yang K,Liu R,Zhu S,Coquinco A,Wen W,Kojic L,Jia W,Cynader M.Isoform-specific palmitoylation of JNK regulates axonal development.Cell Death Differ 2012;19(4):553-561.
8 Yao W,Frie M,Pan J,Pak K,Webster N,Wasserman SI,Ryan AF.C-Jun N-terminal kinase(JNK)isoforms play differing roles in otitis media.BMC Immunol 2014;15:46.
9 Liu C,Zhang CW,Zhou Y,et al.APP upregulation contributes to retinal ganglion cell degeneration via JNK3.Cell Death Differ 2018;25(4):661-676.
10 Grynberg K,Ma FY,Nikolic-Paterson DJ.The JNK signaling pathway in renal fibrosis.Front Phsiol 2017;8:829.
11 Borsello T,Forloni G.JNK signalling:a possible target to prevent neurodegeneration.Curr Pharm Des 2007;13(18):1875-1886.
12 Sabapathy K.Role of the JNK pathway in human diseases.Prog Mol Biol Transl Sci 2012;106:145-169.
13 Pal M,Febbraio MA,Lancaster GI.The roles of C-Jun NH2-terminal kinases(JNKs)in obesity and insulin resistance.J Physiol(Lond)2016;594(2):267-279.
14 Watanabe M,Fukuda Y.Survival and axonal regeneration of retinal ganglion cells in adult cats.Prog Retin Eye Res 2002;21(6):529-553.
15 Almasieh M,Catrinescu MM,Binan L,Costantino S,Levin LA.Axonal degeneration in retinal ganglion cells is associated with a membrane polarity-sensitive redox process.J Neurosci 2017;37(14):3824-3839.
16 Haase G,Pettmann B,Raoul C,Henderson CE.Signaling by death receptors in the nervous system.Curr Opin Neurobiol 2008;18(3):284-291.
17 Selim LA,Hassaan H.Mitochondrial diseases as model of neurodegeneration.Adv Exp Med Biol 2017;1007:129-155.
18 Sessler T,Healy S,Samali A,Szegezdi E.Structural determinants of DISC function:new insights into death receptor-mediated apoptosis signalling.Pharmacol Ther 2013;140:186-199.
19 Gupta R,Ghosh S.Putative roles of mitochondrial voltage-dependent anion channel,Bcl-2 family proteins and c-Jun N-terminal kinases in ischemic stroke associated apoptosis.Biochim Open 2017;4:47-55.
20 Zhang XL,Zhang CX,Wang N,Li Y,Zhang DB,Li Q.MicroRNA-486alleviates hypoxia-induced damage in H9C2 cells by targeting NDRG2to inactivate JNK/C-Jun and NF-κB signaling pathways.Cell Physiol Biochem 2018;48(6):2483-2492.
21 Chang KW,Zong HF,Ma KG,Zhai WY,Yang WN,Hu XD,Xu JH,Chen XL,Ji SF,Qian YH.Activation ofα7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways.Neurochem Int 2018;120:238-250.
22 Chen K,Lu YW,Liu CY,Zhang LM,Fang ZY,Yu GR.Morroniside prevents H2O2 or Aβ1-42-induced apoptosis via attenuating JNK and p38MAPK phosphorylation.Eur J Pharmacol 2018;834:295-304.
23 Dhanasekaran DN,Reddy EP.JNK-signaling:a multiplexing hub in programmed cell death.Genes Cancer 2017;8:682-694.
24 Brecht S,Kirchhof R,Chromik A,et al.Specific pathophysiological functions of JNK isoforms in the brain.Eur J Neurosci 2005;21(2):363-377.
25 Keramaris E,Ruzhynsky VA,Callaghan SM,Wong E,Davis RJ,Flavell R,Slack RS,Park DS.Required roles of Bax and JNKs in central and peripheral nervous system death of retinoblastoma-deficient mice.JBiol Chem 2008;283(1):405-415.
26 Crocker SJ,Hayley SP,Smith PD,Mount MP,Lamba WR,Callaghan SM,Slack RS,Park DS.Regulation of axotomy-induced dopaminergic neuron death and c-jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase.J Neurochem 2006;96(2):489-499.
27 Wen XR,Fu YY,Liu HZ,et al.Neuroprotection of sevoflurane against ischemia/reperfusion-induced brain injury through inhibiting JNK3/caspase-3 by enhancing akt signaling pathway.Mol Neurobiol2016;53:1661-1671.
28 Ambacher KK,Pitzul KB,Karajgikar M,Hamilton A,Ferguson SS,Cregan SP.The JNK-and AKT/GSK3β-signaling pathways converge to regulate puma induction and neuronal apoptosis induced by trophic factor deprivation.PLo S One 2012;7(10):e46885.
29 Zheng J,Qi JG,Zou Q,Zhang ZZ.Construction of PLGA/JNK3-shRNA nanoparticles and their protective role in hippocampal neuron apoptosis induced by oxygen and glucose deprivation.RSC Adc2018;8(36):20108-20116.
30 Maino B,Paparone S,Severini C,Ciotti MT,D’agata V,Calissano P,Cavallaro S.Drug target identification at the crossroad of neuronal apoptosis and survival.Expert Opin Drug Discov 2017;12(3):249-259.
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