Skip to main content

Advertisement

SpringerLink
Log in

CRISPR/Cas9 Editing of Glia Maturation Factor Regulates Mitochondrial Dynamics by Attenuation of the NRF2/HO-1 Dependent Ferritin Activation in Glial Cells

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Microglial cells are brain specific professional phagocytic immune cells that play a crucial role in the inflammation- mediated neurodegeneration especially in Parkinson’s disease (PD) and Alzheimer’s disease. Glia maturation factor (GMF) is a neuroinflammatory protein abundantly expressed in the brain. We have previously shown that GMF expression is significantly upregulated in the substantia nigra (SN) of PD brains. However, its possible role in PD progression is still not fully understood. The Clustered-Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR Associated (Cas) protein9 (CRISPR/Cas9) system is a simple, rapid and often extremely efficient gene editing tool at desired loci, enabling complete gene knockout or homology directed repair. In this study, we examined the effect of GMF editing by using the CRISPR/Cas9 technique in BV2 microglial cells (hereafter referred to as BV2-G) on oxidative stress and nuclear factor erythroid 2-related factor 2 (NRF2)/Hemeoxygenase1 (HO-1)-dependent ferritin activation after treatment with (1-methyl-4-phenylpyridinium) MPP+. Knockout of GMF in BV2-G cells significantly attenuated oxidative stress via reduced ROS production and calcium flux. Furthermore, deficiency of GMF significantly reduced nuclear translocation of NRF2, which modulates HO-1 and ferritin activation, cyclooxygenase 2 (COX2) and nitric oxide synthase 2 (NOS2) expression in BV2 microglial cells. Lack of GMF significantly improved CD11b and CD68 positive microglial cells as compared with untreated cells. Our results also suggest that pharmacological and genetic intervention targeting GMF may represent a promising and a novel therapeutic strategy in controlling Parkinsonism by regulating microglial functions. Targeted regulation of GMF possibly mediates protein aggregation in microglial homeostasis associated with PD progression through regulation of iron metabolism by modulating NRF2-HO1 and ferritin expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127

    Article  PubMed  CAS  Google Scholar 

  • Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421

    Article  PubMed  CAS  Google Scholar 

  • Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10(Suppl):S18–S25

    Article  PubMed  CAS  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  PubMed  CAS  Google Scholar 

  • Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc Natl Acad Sci U S A 106:2933–2938

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen T, Hou R, Xu S, Wu C (2015) Donepezil regulates 1-Methyl-4-phenylpyridinium-induced microglial polarization in Parkinson's disease. ACS Chem Neurosci 6:1708–1714

    Article  PubMed  CAS  Google Scholar 

  • Colton CA, Gilbert DL (1987) Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 223:284–288

    Article  PubMed  CAS  Google Scholar 

  • Colton CA, Chernyshev ON, Gilbert DL, Vitek MP (2000) Microglial contribution to oxidative stress in Alzheimer's disease. Ann N Y Acad Sci 899:292–307

    Article  PubMed  CAS  Google Scholar 

  • Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61:71–90

    Article  PubMed  Google Scholar 

  • Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson's disease. Science 302:819–822

    Article  PubMed  CAS  Google Scholar 

  • De Nuccio C, Bernardo A, De Simone R, Mancuso E, Magnaghi V, Visentin S, Minghetti L (2011) Peroxisome proliferator-activated receptor γ agonists accelerate oligodendrocyte maturation and influence mitochondrial functions and oscillatory Ca2+ waves. J Neuropathol Exp Neurol 70:900–912

    Article  CAS  Google Scholar 

  • de Vries HE, Witte M, Hondius D, Rozemuller AJ, Drukarch B, Hoozemans J, van Horssen J (2008) Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radic Biol Med 45:1375–1383

    Article  PubMed  CAS  Google Scholar 

  • Depaolo RW, Lathan R, Rollins BJ, Karpus WJ (2005) The chemokine CCL2 is required for control of murine gastric Salmonella enterica infection. Infect Immun 73:6514–6522

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ebadi M, Sharma S, Shavali S, El Refaey H (2002) Neuroprotective actions of selegiline. J Neurosci Res 67:285–289

    Article  PubMed  CAS  Google Scholar 

  • Fan B, Dun SH, Gu JQ, Guo Y, Ikuyama S (2015) Pycnogenol attenuates the release of Proinflammatory cytokines and expression of Perilipin 2 in lipopolysaccharide-stimulated microglia in part via inhibition of NF-kappaB and AP-1 activation. PLoS One 10:e0137837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fernandez-Gonzalez A, Perez-Otano I, Morgan JI (2000) MPTP selectively induces haem oxygenase-1 expression in striatal astrocytes. Eur J Neurosci 12:1573–1583

    Article  PubMed  CAS  Google Scholar 

  • Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29:357–365

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goldman SM (2014) Environmental toxins and Parkinson's disease. Annu Rev Pharmacol Toxicol 54:141–164

    Article  PubMed  CAS  Google Scholar 

  • Holmstrom KM, Kostov RV, Dinkova-Kostova AT (2016) The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol 1:80–91

    Article  PubMed  PubMed Central  Google Scholar 

  • Hsieh C-Y, Hsiao H-Y, Wu W-Y, Liu C-A, Tsai Y-C, Chao Y-J, Wang DL, Hsieh H-J (2009) Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells. J Biomed Sci 16:12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hung S-Y, Liou H-C, Kang K-H, Wu R-M, Wen C-C, Fu W-M (2008) Overexpression of Heme Oxygenase-1 protects dopaminergic neurons against 1-Methyl-4-Phenylpyridinium-induced neurotoxicity. Mol Pharmacol 74:1564–1575

    Article  PubMed  CAS  Google Scholar 

  • Hwang JW, Rajendrasozhan S, Yao H, Chung S, Sundar IK, Huyck HL, Pryhuber GS, Kinnula VL, Rahman I (2011) FOXO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. J Immunol 187:987–998

    Article  PubMed  CAS  Google Scholar 

  • Innamorato NG, Rojo AI, García-Yagüe ÁJ, Yamamoto M, de Ceballos ML, Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181:680–689

    Article  PubMed  CAS  Google Scholar 

  • Jenner P, Dexter DT, Sian J, Schapira AH, Marsden CD (1992) Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson's Disease Research Group. Ann Neurol 32(Suppl):S82–S87

    Article  PubMed  CAS  Google Scholar 

  • Kang KW, Lee SJ, Park JW, Kim SG (2002) Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol Pharmacol 62:1001–1010

    Article  PubMed  CAS  Google Scholar 

  • Kaplan R, Zaheer A, Jaye M, Lim R (1991) Molecular cloning and expression of biologically active human glia maturation factor-beta. J Neurochem 57:483–490

    Article  PubMed  CAS  Google Scholar 

  • Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368

    Article  CAS  Google Scholar 

  • Kempuraj D, Khan MM, Thangavel R, Xiong Z, Yang E, Zaheer A (2013) Glia maturation factor induces interleukin-33 release from astrocytes: implications for neurodegenerative diseases. J NeuroImmune Pharmacol 8:643–650

    Article  PubMed  PubMed Central  Google Scholar 

  • Kempuraj D, Selvakumar GP, Zaheer S, Thangavel R, Ahmed ME, Raikwar S, Govindarajan R, Iyer S, Zaheer A (2018) Cross-talk between glia, neurons and mast cells in Neuroinflammation associated with Parkinson's disease. J NeuroImmune Pharmacol 13:100–112

    Article  PubMed  Google Scholar 

  • Khadempar S, Familghadakchi S, Motlagh RA, Farahani N, Dashtiahangar M, Rezaei H, Gheibi Hayat SM (2018) CRISPR–Cas9 in genome editing: its function and medical applications. J Cell Physiol. https://doi.org/10.1002/jcp.27476

    Article  PubMed  CAS  Google Scholar 

  • Khan MM, Kempuraj D, Zaheer S, Zaheer A (2014a) Glia maturation factor deficiency suppresses 1-methyl-4-phenylpyridinium-induced oxidative stress in astrocytes. J Mol Neurosci 53:590–599

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Khan MM, Kempuraj D, Zaheer S, Zaheer A (2014e) Glia maturation factor deficiency suppresses 1-Methyl-4-Phenylpyridinium-induced oxidative stress in astrocytes. J Mol Neurosci 53:590–599

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med 38:333–347

    Article  PubMed  CAS  Google Scholar 

  • Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–70

    Article  PubMed  CAS  Google Scholar 

  • Lim R, Zaheer A, Lane WS (1990) Complete amino acid sequence of bovine glia maturation factor beta. Proc Natl Acad Sci U S A 87:5233–5237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu K, Liu PC, Liu R, Wu X (2015) Dual AO/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry. Med Sci Monit Basic Res 21:15–20

    Article  PubMed  PubMed Central  Google Scholar 

  • Lunov O, Zablotskii V, Churpita O, Chánová E, Syková E, Dejneka A, Kubinová Š (2014) Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations. Sci Rep 4:7129

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • MacNamara KC, Oduro K, Martin O, Jones DD, McLaughlin M, Choi K, Borjesson DL, Winslow GM (2011) Infection-induced myelopoiesis during intracellular bacterial infection is critically dependent upon IFN-gamma signaling. J Immunol 186:1032–1043

    Article  PubMed  CAS  Google Scholar 

  • Miklya I, Pencz N, Hafenscher F, Goltl P (2014) The role of alpha-synuclein in Parkinson's disease. Neuropsychopharmacol Hung 16:77–84

    PubMed  Google Scholar 

  • Morris GP, Clark IA, Zinn R, Vissel B (2013) Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiol Learn Mem 105:40–53

    Article  PubMed  CAS  Google Scholar 

  • Olanow CW, Schapira AH (2013) Therapeutic prospects for Parkinson disease. Ann Neurol 74(3):337–347

    Article  PubMed  CAS  Google Scholar 

  • Park SY, Kim HS, Cho EK, Kwon BY, Phark S, Hwang KW, Sul D (2008) Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem Toxicol 46:2881–2887

    Article  PubMed  CAS  Google Scholar 

  • Park SJ, Lee JH, Kim HY, Choi YH, Park JS, Suh YH, Park SM, E-h J, Jou I (2012) Astrocytes, but not microglia, rapidly sense H<sub>2</sub>O<sub>2</sub> via STAT6 phosphorylation, resulting in Cyclooxygenase-2 expression and prostaglandin release. J Immunol 188:5132–5141

    Article  PubMed  CAS  Google Scholar 

  • Perry VH, Teeling J (2013) Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35:601–612

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201

    Article  PubMed  Google Scholar 

  • Petrache I, Otterbein LE, Alam J, Wiegand GW, Choi AM (2000) Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol 278:L312–L319

    Article  PubMed  CAS  Google Scholar 

  • Prasad KN, Cole WC, Kumar B (1999) Multiple antioxidants in the prevention and treatment of Parkinson's disease. J Am Coll Nutr 18:413–423

    Article  PubMed  CAS  Google Scholar 

  • Raikwar SP, Thangavel R, Dubova I, Ahmed ME, Selvakumar PG, Kempuraj D, Zaheer S, Iyer S, Zaheer A (2018a) Neuro-Immuno-gene- and Genome-editing-therapy for Alzheimer's disease: are we there yet? J Alzheimers Dis 65:321–344

    Article  PubMed  PubMed Central  Google Scholar 

  • Raikwar SP, Thangavel R, Dubova I, Selvakumar GP, Ahmed ME, Kempuraj D, Zaheer SA, Iyer SS, Zaheer A (2018b) Targeted gene editing of glia maturation factor in microglia: a novel Alzheimer’s disease therapeutic target. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1068-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reeve A, Simcox E, Turnbull D (2014) Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Ageing Res Rev 14:19–30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ribble D, Goldstein NB, Norris DA, Shellman YG (2005) A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol 5:12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851

    Article  PubMed  CAS  Google Scholar 

  • Sareen D, Darjatmoko SR, Albert DM, Polans AS (2007) Mitochondria, calcium, and calpain are key mediators of resveratrol-induced apoptosis in breast cancer. Mol Pharmacol 72:1466–1475

    Article  PubMed  CAS  Google Scholar 

  • Scapagnini G, Vasto S, Abraham NG, Caruso C, Zella D, Fabio G (2011) Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol 44:192–201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schipper HM, Song W (2015) A heme oxygenase-1 transducer model of degenerative and developmental brain disorders. Int J Mol Sci 16:5400–5419

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Selvakumar GP, Iyer SS, Kempuraj D, Raju M, Thangavel R, Saeed D, Ahmed ME, Zahoor H, Raikwar SP, Zaheer S, Zaheer A (2018) Glia maturation factor dependent inhibition of mitochondrial PGC-1α triggers oxidative stress-mediated apoptosis in N27 rat dopaminergic neuronal cells. Mol Neurobiol 55(9):7132–7152

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Soto MS, Sibson NR (2018) The multifarious role of microglia in brain metastasis. Front Cell Neurosci 12:414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Strom J, Xu B, Tian X, Chen QM (2016) Nrf2 protects mitochondrial decay by oxidative stress. FASEB J 30:66–80

    Article  PubMed  CAS  Google Scholar 

  • Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A (2015) Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of Heme Oxygenase-1. PLoS One 10:e0141509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Valente EM et al (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:1158–1160

    Article  PubMed  CAS  Google Scholar 

  • Vile GF, Tyrrell RM (1993) Oxidative stress resulting from ultraviolet a irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin. J Biol Chem 268:14678–14681

    Article  PubMed  CAS  Google Scholar 

  • Weiss G, Werner-Felmayer G, Werner ER, Grunewald K, Wachter H, Hentze MW (1994) Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med 180:969–976

    Article  PubMed  CAS  Google Scholar 

  • Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R (2007) Inflammation in Parkinson's diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des 13:1925–1928

    Article  PubMed  CAS  Google Scholar 

  • Wirenfeldt M, Dissing-Olesen L, Anne Babcock A, Nielsen M, Meldgaard M, Zimmer J, Azcoitia I, Leslie RG, Dagnaes-Hansen F, Finsen B (2007) Population control of resident and immigrant microglia by mitosis and apoptosis. Am J Pathol 171:617–631

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015) Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 36:605–613

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu L, He D, Bai Y (2016) Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol 53:6709–6715

    Article  PubMed  CAS  Google Scholar 

  • Yin J, Valin KL, Dixon ML, Leavenworth JW (2017) The role of microglia and macrophages in CNS homeostasis, autoimmunity, and cancer. J Immunol Res 2017:5150678

    PubMed  PubMed Central  Google Scholar 

  • Yu H, Liu Z, Zhou H, Dai W, Chen S, Shu Y, Feng J (2012) JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress. Neurosci Lett 529:166–171

    Article  PubMed  CAS  Google Scholar 

  • Zaheer A, Fink BD, Lim R (1993) Expression of glia maturation factor beta mRNA and protein in rat organs and cells. J Neurochem 60:914–920

    Article  PubMed  CAS  Google Scholar 

  • Zaheer S, Wu Y, Bassett J, Yang B, Zaheer A (2007) Glia maturation factor regulation of STAT expression: a novel mechanism in experimental autoimmune encephalomyelitis. Neurochem Res 32:2123–2131

    Article  PubMed  CAS  Google Scholar 

  • Zaheer A, Zaheer S, Thangavel R, Wu Y, Sahu SK, Yang B (2008) Glia maturation factor modulates beta-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage. Brain Res 1208:192–203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zaheer S, Wu Y, Sahu SK, Zaheer A (2011) Suppression of neuro inflammation in experimental autoimmune encephalomyelitis by glia maturation factor antibody. Brain Res 1373:230–239

    Article  PubMed  CAS  Google Scholar 

  • Zhou P, Weng R, Chen Z, Wang R, Zou J, Liu X, Liao J, Wang Y, Xia Y, Wang Q (2016) TLR4 signaling in MPP(+)-induced activation of BV-2 cells. Neural Plast 2016:5076740

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Veteran Affairs Merit award I01BX002477 and National Institutes of Health grant AG048205 to AZ.

Author information

Authors and Affiliations

  1. Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA

    Govindhasamy Pushpavathi Selvakumar, Mohammad Ejaz Ahmed, Ramasamy Thangavel, Duraisamy Kempuraj, Iuliia Dubova, Shankar Iyer & Asgar Zaheer

  2. Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, USA

    Govindhasamy Pushpavathi Selvakumar, Mohammad Ejaz Ahmed, Sudhanshu P. Raikwar, Ramasamy Thangavel, Duraisamy Kempuraj, Iuliia Dubova, Daniyal Saeed, Haris Zahoor, Keerthivaas Premkumar, Smita Zaheer, Shankar Iyer & Asgar Zaheer

Authors
  1. Govindhasamy Pushpavathi Selvakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Ejaz Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sudhanshu P. Raikwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramasamy Thangavel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Duraisamy Kempuraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Iuliia Dubova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniyal Saeed
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haris Zahoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Keerthivaas Premkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Smita Zaheer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shankar Iyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Asgar Zaheer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Asgar Zaheer.

Ethics declarations

Conflict of Interest

The authors declare that there are no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Selvakumar, G.P., Ahmed, M.E., Raikwar, S.P. et al. CRISPR/Cas9 Editing of Glia Maturation Factor Regulates Mitochondrial Dynamics by Attenuation of the NRF2/HO-1 Dependent Ferritin Activation in Glial Cells. J Neuroimmune Pharmacol 14, 537–550 (2019). https://doi.org/10.1007/s11481-019-09833-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-019-09833-6

Keywords

Search

Navigation