Targeting astrocytic CLC2(CLCN2) restores myelin regeneration through inhibition of SPP1/CD44 signaling pathway in leukoencephalopathy

  • van der Knaap MS, Schiffmann R, Mochel F, Wolf NI. Diagnosis, prognosis, and treatment of leukodystrophies. Lancet Neurol. 2019;18:962–72.

    PubMed 

    Google Scholar 

  • Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, et al. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab. 2015;114:494–500.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Elbaz B, Popko B. Molecular control of oligodendrocyte development. Trends Neurosci. 2019;42:263–77.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Verkhratsky A, Parpura V. Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis. 2016;85:254–61.

    PubMed 

    Google Scholar 

  • Molina-Gonzalez I, Holloway RK, Jiwaji Z, Dando O, Kent SA, Emelianova K, et al. Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration. Nat Commun. 2023;14:3372.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Neel DV, Basu H, Gunner G, Bergstresser MD, Giadone RM, Chung H, et al. Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration. Neuron. 2023;111:1222–40.e9.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kakae M, Nakajima H, Tobori S, Kawashita A, Miyanohara J, Morishima M, et al. The astrocytic TRPA1 channel mediates an intrinsic protective response to vascular cognitive impairment via LIF production. Sci Adv. 2023;9:eadh0102.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hammond TR, Gadea A, Dupree J, Kerninon C, Nait-Oumesmar B, Aguirre A, et al. Astrocyte-derived endothelin-1 inhibits remyelination through notch activation. Neuron. 2014;81:588–602.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, et al. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci. 2007;27:6581–9.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bi MM, Hong S, Zhou HY, Wang HW, Wang LN, Zheng YJ. Chloride channelopathies of ClC-2. Int J Mol Sci. 2013;15:218–49.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Hoegg-Beiler MB, Sirisi S, Orozco IJ, Ferrer I, Hohensee S, Auberson M, et al. Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nat Commun. 2014;5:3475.

    PubMed 

    Google Scholar 

  • Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013;12:659–68.

    CAS 
    PubMed 

    Google Scholar 

  • Elorza-Vidal X, Gaitán-Peñas H, Estévez R. Chloride channels in astrocytes: structure, roles in brain homeostasis and implications in disease. Int J Mol Sci. 2019;20:1034.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guo Z, Lu T, Peng L, Cheng H, Peng F, Li J, et al. CLCN2-related leukoencephalopathy: a case report and review of the literature. BMC Neurol. 2019;19:156.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Holla VV, Phulpagar P, Saini J, Kamble N, Pal PK, Yadav R, et al. CLCN2-related leukoencephalopathy in two unrelated patients due to novel variants. Mov Disord Clin Pract. 2023;10:1155–8.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Gaitán-Peñas H, Apaja PM, Arnedo T, Castellanos A, Elorza-Vidal X, Soto D, et al. Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl(−) channel function and trafficking. J Physiol. 2017;595:6993–7008.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Göppner C, Soria AH, Hoegg-Beiler MB, Jentsch TJ. Cellular basis of ClC-2 Cl(−) channel-related brain and testis pathologies. J Biol Chem. 2021;296:100074.

    PubMed 

    Google Scholar 

  • van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134:351–82.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen Z, Peng F, Liu J, Xie B, Xu P, Gan Z, et al. Generation of an iPSC line (SKLOi001-A) from a patient with CLCN2-related leukoencephalopathy. Stem Cell Res. 2020;45:101769.

    CAS 
    PubMed 

    Google Scholar 

  • Xu P, Chen Z, Ma J, Shan Y, Wang Y, Xie B, et al. Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. Hum Genet. 2023;142:577–93.

    CAS 
    PubMed 

    Google Scholar 

  • Cheng Y, Liu X, Sun L, Ding X. Case report: a frameshift mutation in CLCN2-related leukoencephalopathy and retinopathy. Front Genet. 2023;14:1278961.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Luo W, Xu H, Xu L, Jiang W, Chen C, Chang Y, et al. Remyelination in neuromyelitis optica spectrum disorder is promoted by edaravone through mTORC1 signaling activation. Glia. 2023;71:284–304.

    CAS 
    PubMed 

    Google Scholar 

  • Ding L, Zhou J, Ye L, Sun Y, Jiang Z, Gan D, et al. PPAR-γ Is critical for HDAC3-mediated control of oligodendrocyte progenitor cell proliferation and differentiation after focal demyelination. Mol Neurobiol. 2020;57:4810–24.

    CAS 
    PubMed 

    Google Scholar 

  • Xie Y, Chen X, Li Y, Chen S, Liu S, Yu Z, et al. Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways. J Neuroinflamm. 2022;19:194.

    CAS 

    Google Scholar 

  • Lee HG, Rone JM, Li Z, Akl CF, Shin SW, Lee JH, et al. Disease-associated astrocyte epigenetic memory promotes CNS pathology. Nature. 2024;627:865–72.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J, et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature. 2021;597:709–14.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature. 2019;573:75–82.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li L, Tian E, Chen X, Chao J, Klein J, Qu Q, et al. GFAP mutations in astrocytes impair oligodendrocyte progenitor proliferation and myelination in an hiPSC model of alexander disease. Cell Stem Cell. 2018;23:239–51.e236.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Świderek-Matysiak M, Oset M, Domowicz M, Galazka G, Namiecińska M, Stasiołek M. Cerebrospinal fluid biomarkers in differential diagnosis of multiple sclerosis and systemic inflammatory diseases with central nervous system involvement. Biomedicines. 2023;11:425.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Marastoni D, Magliozzi R, Bolzan A, Pisani AI, Rossi S, Crescenzo F, et al. CSF levels of CXCL12 and osteopontin as early markers of primary progressive multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8:e1083.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Marastoni D, Turano E, Tamanti A, Colato E, Pisani AI, Scartezzini A, et al. Association of levels of CSF osteopontin with cortical atrophy and disability in early multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2024;11:e200265.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Börnsen L, Khademi M, Olsson T, Sørensen PS, Sellebjerg F. Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis. Mult Scler. 2011;17:32–42.

    PubMed 

    Google Scholar 

  • de Luna N, Carbayo Á, Dols-Icardo O, Turon-Sans J, Reyes-Leiva D, Illan-Gala I, et al. Neuroinflammation-related proteins NOD2 and Spp1 are abnormally upregulated in amyotrophic lateral sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023;10:e200072.

    PubMed 

    Google Scholar 

  • Quesnel MJ, Labonté A, Picard C, Bowie DC, Zetterberg H, Blennow K, et al. Osteopontin: a novel marker of pre-symptomatic sporadic Alzheimer’s disease. Alzheimers Dement. 2024;20:6008–31.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tredicine M, Camponeschi C, Pirolli D, Lucchini M, Valentini M, Geloso MC, et al. A TLR/CD44 axis regulates T cell trafficking in experimental and human multiple sclerosis. iScience. 2022;25:103763.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Marcondes MC, Ojakian R, Bortell N, Flynn C, Conti B, Fox HS. Osteopontin expression in the brain triggers localized inflammation and cell death when immune cells are activated by pertussis toxin. Mediators Inflamm. 2014;2014:358218.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Tuohy TM, Wallingford N, Liu Y, Chan FH, Rizvi T, Xing R, et al. CD44 overexpression by oligodendrocytes: a novel mouse model of inflammation-independent demyelination and dysmyelination. Glia. 2004;47:335–45.

    PubMed 

    Google Scholar 

  • Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med. 2005;11:966–72.

    CAS 
    PubMed 

    Google Scholar 

  • Ma XR, Zhu X, Xiao Y, Gu HM, Zheng SS, Li L, et al. Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing. Nat Commun. 2022;13:1225.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012;487:443–8.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Olabarria M, Goldman JE. Disorders of astrocytes: alexander disease as a model. Annu Rev Pathol. 2017;12:131–52.

    CAS 
    PubMed 

    Google Scholar 

  • Schlett JS, Mettang M, Skaf A, Schweizer P, Errerd A, Mulugeta EA, et al. NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss. Mol Neurodegener. 2023;18:24.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Monje M. Myelin plasticity and nervous system function. Annu Rev Neurosci. 2018;41:61–76.

    CAS 
    PubMed 

    Google Scholar 

  • Rojo D, Dal Cengio L, Badner A, Kim S, Sakai N, Greene J, et al. BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep. Neuron. 2023;111:3604–18.e3611.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci. 2001;21:5429–38.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Park H, Han KS, Oh SJ, Jo S, Woo J, Yoon BE, et al. High glutamate permeability and distal localization of Best1 channel in CA1 hippocampal astrocyte. Mol Brain. 2013;6:54.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Edwards MM, Marín de Evsikova C, Collin GB, Gifford E, Wu J, Hicks WL, et al. Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. Invest Ophthalmol Vis Sci. 2010;51:3264–72.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet. 2018;50:349–54.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mitsuda M, Shiozaki A, Kudou M, Shimizu H, Arita T, Kosuga T, et al. Functional analysis and clinical significance of chloride channel 2 expression in esophageal squamous cell carcinoma. Ann Surg Oncol. 2021;28:5384–97.

    PubMed 

    Google Scholar 

  • Di Bella D, Pareyson D, Savoiardo M, Farina L, Ciano C, Caldarazzo S, et al. Subclinical leukodystrophy and infertility in a man with a novel homozygous CLCN2 mutation. Neurology. 2014;83:1217–8.

    PubMed 

    Google Scholar 

  • Wang H, Xu M, Kong Q, Sun P, Yan F, Tian W, et al. Research and progress on ClC‑2 (Review). Mol Med Rep. 2017;16:11–22.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Giorgio E, Vaula G, Benna P, Lo Buono N, Eandi CM, Dino D, et al. A novel homozygous change of CLCN2 (p.His590Pro) is associated with a subclinical form of leukoencephalopathy with ataxia (LKPAT). J Neurol Neurosurg Psychiatry. 2017;88:894–6.

    PubMed 

    Google Scholar 

  • D’Agostino D, Bertelli M, Gallo S, Cecchin S, Albiero E, Garofalo PG, et al. Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy. Neurology. 2004;63:1500–2.

    PubMed 

    Google Scholar 

  • Plazaola-Sasieta H, Zhu Q, Gaitán-Peñas H, Rios M, Estévez R, Morey M. Drosophila ClC-a is required in glia of the stem cell niche for proper neurogenesis and wiring of neural circuits. Glia. 2019;67:2374–98.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Cortez MA, Li C, Whitehead SN, Dhani SU, D’Antonio C, Huan LJ, et al. Disruption of ClC-2 expression is associated with progressive neurodegeneration in aging mice. Neuroscience. 2010;167:154–62.

    CAS 
    PubMed 

    Google Scholar 

  • Sirisi S, Elorza-Vidal X, Arnedo T, Armand-Ugón M, Callejo G, Capdevila-Nortes X, et al. Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes: implications in megalencephalic leukoencephalopathy. Hum Mol Genet. 2017;26:2436–50.

    CAS 
    PubMed 

    Google Scholar 

  • Walker-Caulfield ME, Guo Y, Johnson RK, McCarthy CB, Fitz-Gibbon PD, Lucchinetti CF, et al. NFκB signaling drives pro-granulocytic astroglial responses to neuromyelitis optica patient IgG. J Neuroinflamm. 2015;12:185.

    Google Scholar 

  • Yang SX, Zhang ZC, Bai HL. ClC-5 alleviates renal fibrosis in unilateral ureteral obstruction mice. Hum Cell. 2019;32:297–305.

    CAS 
    PubMed 

    Google Scholar 

  • Liu D, He H, Li GL, Chen J, Yin D, Liao ZP, et al. Mechanisms of chloride in cardiomyocyte anoxia-reoxygenation injury: the involvement of oxidative stress and NF-kappaB activation. Mol Cell Biochem. 2011;355:201–9.

    CAS 
    PubMed 

    Google Scholar 

  • Deng G, Zeng F, Su J, Zhao S, Hu R, Zhu W, et al. BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway. Theranostics. 2020;10:11428–43.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lopes KP, Yu L, Shen X, Qiu Y, Tasaki S, Iatrou A, et al. Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults. Alzheimers Dement. 2024;20:525–37.

    CAS 
    PubMed 

    Google Scholar 

  • Murugaiyan G, Mittal A, Weiner HL. Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J Immunol. 2008;181:7480–8.

    CAS 
    PubMed 

    Google Scholar 

  • Spitzer D, Guérit S, Puetz T, Khel MI, Armbrust M, Dunst M, et al. Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke. Acta Neuropathol. 2022;144:305–37.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cappellano G, Vecchio D, Magistrelli L, Clemente N, Raineri D, Barbero Mazzucca C, et al. The Yin-Yang of osteopontin in nervous system diseases: damage versus repair. Neural Regen Res. 2021;16:1131–7.

    CAS 
    PubMed 

    Google Scholar 

  • Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science. 2001;294:1731–5.

    CAS 
    PubMed 

    Google Scholar 

  • Clemente N, Comi C, Raineri D, Cappellano G, Vecchio D, Orilieri E, et al. Role of anti-osteopontin antibodies in multiple sclerosis and experimental autoimmune encephalomyelitis. Front Immunol. 2017;8:321.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Lan Y, Zhang X, Liu S, Guo C, Jin Y, Li H, et al. Fate mapping of Spp1 expression reveals age-dependent plasticity of disease-associated microglia-like cells after brain injury. Immunity. 2024;57:349–63.e349.

    CAS 
    PubMed 

    Google Scholar 

  • Luo M, Qiu Z, Tang X, Wu L, Li S, Zhu J, et al. Inhibiting cyclin B1-treated pontine infarction by suppressing proliferation of SPP1+ microglia. Mol Neurobiol. 2023;60:1782–96.

    CAS 
    PubMed 

    Google Scholar 

  • De Schepper S, Ge JZ, Crowley G, Ferreira LSS, Garceau D, Toomey CE, et al. Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease. Nat Neurosci. 2023;26:406–15.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Boonpraman N, Yoon S, Kim CY, Moon JS, Yi SS. NOX4 as a critical effector mediating neuroinflammatory cytokines, myeloperoxidase and osteopontin, specifically in astrocytes in the hippocampus in Parkinson’s disease. Redox Biol. 2023;62:102698.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jakovac H, Grubić Kezele T, Šućurović S, Mulac-Jeričević B, Radošević-Stašić B. Osteopontin-metallothionein I/II interactions in experimental autoimmune encephalomyelitis. Neuroscience. 2017;350:133–45.

    CAS 
    PubMed 

    Google Scholar 

  • Schröder LJ, Mulenge F, Pavlou A, Skripuletz T, Stangel M, Gudi V, et al. Dynamics of reactive astrocytes fosters tissue regeneration after cuprizone-induced demyelination. Glia. 2023;71:2573–90.

    PubMed 

    Google Scholar 

  • Dzwonek J, Wilczynski GM. CD44: molecular interactions, signaling and functions in the nervous system. Front Cell Neurosci. 2015;9:175.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Sato T, Shirai R, Isogai M, Yamamoto M, Miyamoto Y, Yamauchi J. Hyaluronic acid and its receptor CD44, acting through TMEM2, inhibit morphological differentiation in oligodendroglial cells. Biochem Biophys Res Commun. 2022;624:102–11.

    CAS 
    PubMed 

    Google Scholar 

  • Dooves S, Bugiani M, Postma NL, Polder E, Land N, Horan ST, et al. Astrocytes are central in the pathomechanisms of vanishing white matter. J Clin Invest. 2016;126:1512–24.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Quintela-López T, Ortiz-Sanz C, Serrano-Regal MP, Gaminde-Blasco A, Valero J, Baleriola J, et al. Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling. Cell Death Dis. 2019;10:445.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jiang W, Zhu F, Xu H, Xu L, Li H, Yang X, et al. CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation. Sci Adv. 2023;9:eadg8148.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Song Y, Jiang W, Afridi SK, Wang T, Zhu F, Xu H, et al. Astrocyte-derived CHI3L1 signaling impairs neurogenesis and cognition in the demyelinated hippocampus. Cell Rep. 2024;43:114226.

    CAS 
    PubMed 

    Google Scholar 

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