Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system

Journal of Neuroinflammation

Myriam Baes⁴  Rita Devos³  Wilhelm Just¹  Paul P Van Veldhoven²  Simon Verheijden⁴  Astrid Bottelbergs⁴ 

[1] Heidelberg Center of Biochemistry, University of Heidelberg, Heidelberg, Germany;LIPIT, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium;Department of Pathology, K.U.Leuven, Leuven, Belgium;Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U.Leuven, Leuven, Belgium

关键词: Macrophage;    Inflammation;    Axonal degeneration;    Demyelination;    Complement;    Plasmalogens;    Mouse models;    Peroxisomes;   

Others  :  1212703
DOI  :  10.1186/1742-2094-9-61

 received in 2011-11-22, accepted in 2012-03-29,  发布年份 2012

【 摘 要 】

Background

Mice with peroxisome deficiency in neural cells (Nestin-Pex5^−/−) develop a neurodegenerative phenotype leading to motor and cognitive disabilities and early death. Major pathologies at the end stage of disease include severe demyelination, axonal degeneration and neuroinflammation. We now investigated the onset and progression of these pathological processes, and their potential interrelationship. In addition, the putative role of oxidative stress, the impact of plasmalogen depletion on the neurodegenerative phenotype, and the consequences of peroxisome elimination in the postnatal period were studied.

Methods

Immunohistochemistry in association with gene expression analysis was performed on Nestin-Pex5^−/− mice to document demyelination, axonal damage and neuroinflammation. Also Gnpat^−/− mice, with selective plasmalogen deficiency and CMV-Tx-Pex5^−/− mice, with tamoxifen induced generalized loss of peroxisomes were analysed.

Results

Activation of the innate immune system is a very early event in the pathological process in Nestin-Pex5^−/− mice which evolves in chronic neuroinflammation. The complement factor C1q, one of the earliest up regulated transcripts, was expressed on neurons and oligodendrocytes but not on microglia. Transcripts of other pro- and anti-inflammatory genes and markers of phagocytotic activity were already significantly induced before detecting pathologies with immunofluorescent staining. Demyelination, macrophage activity and axonal loss co-occurred throughout the brain. As in patients with mild peroxisome biogenesis disorders who develop regressive changes, demyelination in cerebellum and brain stem preceded major myelin loss in corpus callosum of both Nestin-Pex5^−/− and CMV-Tx-Pex5^−/− mice. These lesions were not accompanied by generalized oxidative stress throughout the brain. Although Gnpat^−/− mice displayed dysmyelination and Purkinje cell axon damage in cerebellum, confirming previous observations, no signs of inflammation or demyelination aggravating with age were observed.

Conclusions

Peroxisome inactivity triggers a fast neuroinflammatory reaction, which is not solely due to the depletion of plasmalogens. In association with myelin abnormalities this causes axon damage and loss.

【 授权许可】

   
2012 Bottelbergs et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Steinberg S, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW: Peroxisome biogenesis disorders. Biochim Biophys Acta 2006, 1763:1733-1748.
• [2]Wanders RJ, Waterham HR: Peroxisomal disorders: the single peroxisomal enzyme deficiencies. Biochim Biophys Acta 2006, 1763:1707-1720.
• [3]Baes M, Aubourg P: Peroxisomes, myelination, and axonal integrity in the CNS. Neuroscientist 2009, 15:367-379.
• [4]Hulshagen L, Krysko O, Huyghe S, Klein R, Van Veldhoven PP, De Deyn PP, D’hooge R, Hartmann D, Baes M: Absence of functional peroxisomes from mouse central nervous system causes dysmyelination and axon degeneration. J Neurosci 2008, 28:4015-4027.
• [5]Krysko O, Hulshagen L, Janssen A, Schutz G, Klein R, De Bruycker M, Espeel M, Gressens P, Baes M: Neocortical and cerebellar developmental abnormalities in conditions of selective elimination of peroxisomes from brain or from liver. J Neurosci Res 2007, 85:58-72.
• [6]Kassmann CM, Lappe-Siefke C, Baes M, Brügger B, Mildner A, Werner HB, Natt O, Michaelis T, Prinz M, Frahm J, Nave K-A: Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet 2007, 39:969-976.
• [7]Bottelbergs A, Verheijden S, Hulshagen L, Gutmann DH, Goebbels S, Nave KA, Kassmann C, Baes M: Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes. GLIA 2010, 58(13):1532-1543.
• [8]Rodemer C, Thai TP, Brugger B, Kaercher T, Werner H, Nave KA, Wieland F, Gorgas K, Just WW: Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum Mol Genet 2003, 12:1881-1895.
• [9]Teigler A, Komijenovic D, Draguhn A, Gorgas K, Just WW: Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebrum. Hum Mol Genet 2009, 18:1897-1908.
• [10]Fourcade S, Lopez-Erauskin J, Galino J, Duval C, Naudi A, Jove M, Kemp S, Villarroya F, Ferrer I, Pamplona R, Portero-Otin M, Pujol A: Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum Mol Genet 2008, 17:1762-1773.
• [11]Galino J, Ruiz M, Fourcade S, Schluter A, Lopez-Erauskin J, Guilera C, Jove M, Naudi A, Garcia-Arumi E, Andreu AL, Starkov AA, Pamplona R, Ferrer I, Portero-Otin M, Pujol A: Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-adrenoleukodystrophy. Antioxid Redox Signal 2011, 15(8):2095-2107.
• [12]Muller CC, Nguyen TH, Ahlemeyer B, Meshram M, Santrampurwala N, Cao S, Sharp P, Fietz PB, Baumgart-Vogt E, Crane DI: PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress. Dis Model Mech 2011, 4(1):104-119.
• [13]Huyghe S, Mannaerts GP, Baes M, Van Veldhoven PP: Peroxisomal multifunctional protein-2: the enzyme, the patients and the knockout mouse model. Biochim Biophys Acta 2006, 1761:973-994.
• [14]Huyghe S, Schmalbruch H, Hulshagen L, Van Veldhoven PP, Baes M, Hartmann D: Peroxisomal multifunctional protein-2 deficiency causes motor deficits and glial lesions in the adult CNS. Am J Pathol 2006, 168:1321-1334.
• [15]Hayashi S, McMahon AP: Efficient recombination in diverse tissues by a tamoxifen-iniducible form of Cre: a tool for temporally regulated Cre activation/inactivation in the mouse. Dev Biol 2002, 244:305-318.
• [16]Martens K, Ver Loren Van Themaat E, van Batenburg MF, Heinaniemi M, Huyghe S, Van Hummelen P, Carlberg C, van Veldhoven PP, Van Kampen A, Baes M: Coordinate induction of PPAR alpha and SREBP2 in multifunctional protein 2 deficient mice. Biochim Biophys Acta 2008, 1781(11–12):694-702.
• [17]Fernandes CG, Leipnitz G, Seminotti B, Amaral AU, Zanatta A, Vargas CR, Dutra Filho CS, Wajner M: Experimental evidence that phenylalanine provokes oxidative stress in hippocampus and cerebral cortex of developing rats. Cell Mol Neurobiol 2010, 30(2):317-326.
• [18]Gay C, Collins J, Gebicki JM: Hydroperoxide assay with the ferric-xylenol orange complex. Anal Biochem 1999, 273(2):149-155.
• [19]Howell OW, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora AJ, Brophy PJ, Reynolds R: Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 2006, 129(Pt 12):3173-3185.
• [20]Coman I, Aigrot MS, Seilhean D, Reynolds R, Girault JA, Zalc B, Lubetzki C: Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 2006, 129:3186-3195.
• [21]Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K: UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 2007, 446:1091-1095.
• [22]Ellett F, Pase L, Hayman JW, Andrianopoulos A, Lieschke GJ: mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish. Blood 2011, 117(4):e49-e56.
• [23]Min KJ, Yang MS, Kim SU, Jou I, Joe EH: Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J Neurosci 2006, 26(6):1880-1887.
• [24]Innamorato NG, Lastres-Becker I, Cuadrado A: Role of microglial redox balance in modulation of neuroinflammation. Curr Opin Neurol 2009, 22(3):308-314.
• [25]Colton CA, Wilcock DM: Assessing activation states in microglia. CNS Neurol Disord Drug Targets 2010, 9(2):174-191.
• [26]Moreira PI, Sayre LM, Zhu X, Nunomura A, Smith MA, Perry G: Detection and localization of markers of oxidative stress by in situ methods: application in the study of Alzheimer disease. Methods Mol Biol 2010, 610:419-434.
• [27]Rubbo H, Radi R: Protein and lipid nitration: role in redox signaling and injury. Biochim Biophys Acta 2008, 1780(11):1318-1324.
• [28]Liu W, Tang Y, Feng J: Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 2011, 89(5–6):141-146.
• [29]Schwartz M, Butovsky O, Bruck W, Hanisch UK: Microglial phenotype: is the commitment reversible? Trends Neurosci 2006, 29(2):68-74.
• [30]Rojo AI, Innamorato NG, Martin-Moreno AM, De Ceballos ML, Yamamoto M, Cuadrado A: Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia 2010, 58(5):588-598.
• [31]Mast FD, Li J, Virk MK, Hughes SC, Simmonds AJ, Rachubinski RA: A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders. Dis Model Mech 2011, 4(5):659-672.
• [32]Dixit E, Boulant S, Zhang Y, Lee AS, Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan SP, Fransen M, Nibert ML, Superti-Furga G, Kagan JC: Peroxisomes are signaling platforms for antiviral innate immunity. Cell 2010, 141(4):668-681.
• [33]Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD: Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 2000, 48(6):893-901.
• [34]Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H: The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009, 132(Pt 5):1175-1189.
• [35]Barth PG, Majoie CB, Gootjes J, Wanders RJ, Waterham HR, van der Knaap MS, de Klerk JB, Smeitink J, Poll-The BT: Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 2004, 62:439-444.
• [36]Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA, Dekker CJ, Spooner C, Ngu LH, De Sousa C, Wanders RJ, Fietz MJ, Clayton PT, Waterham HR, Ferdinandusse S: Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet 2010, 47(9):608-615.
• [37]Sevin C, Ferdinandusse S, Waterham HR, Wanders RJ, Aubourg P: Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene. Orphanet J Rare Dis 2011, 6:8. BioMed Central Full Text
• [38]Regal L, Ebberink MS, Goemans N, Wanders RJ, De ML, Jaeken J, Schrooten M, Van Coster R, Waterham HR: Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol 2010, 68(2):259-263.
• [39]Bams-Mengerink AM, Majoie CB, Duran M, Wanders RJ, Van Hove J, Scheurer CD, Barth PG, Poll-The BT: MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata. Neurology 2006, 66:798-803.
• [40]Brites P, Mooyer PAW, el Mrabet L, Duran M, Waterham HR, Wanders RJA: Plasmalogens participate in very-long-chain fatty acid-induced pathology. Brain 2009, 132:482-492.
• [41]Powers JM, Moser HW: Peroxisomal disorders : genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 1998, 8:101-120.
• [42]Viola A, Confort-Gouny S, Ranjeva JP, Chabrol B, Raybaud C, Vintila F, Cozzone PJ: MR imaging and MR spectroscopy in rhizomelic chondrodysplasia punctata. AJNR Am J Neuroradiol 2002, 23:480-483.
• [43]Powers JM: Demyelination in peroxisomal diseases. J Neurol Sci 2005, 228:206-207.
• [44]Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W: Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002, 125(Pt 10):2202-2212.
• [45]Anderson AJ, Robert S, Huang W, Young W, Cotman CW: Activation of complement pathways after contusion-induced spinal cord injury. J Neurotrauma 2004, 21(12):1831-1846.
• [46]Yasojima K, Schwab C, McGeer EG, McGeer PL: Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol 1999, 154(3):927-936.
• [47]Lopez-Erauskin J, Fourcade S, Galino J, Ruiz M, Schluter A, Naudi A, Jove M, Portero-Otin M, Pamplona R, Ferrer I, Pujol A: Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann Neurol 2011, 70(1):84-92.
• [48]Deon M, Sitta A, Barschak AG, Coelho DM, Pigatto M, Schmitt GO, Jardim LB, Giugliani R, Wajner M, Vargas CR: Induction of lipid peroxidation and decrease of antioxidant defenses in symptomatic and asymptomatic patients with X-linked adrenoleukodystrophy. Int J Dev Neurosci 2007, 25(7):441-444.
• [49]Ferdinandusse S, Finckh B, de Hingh YC, Stroomer LE, Denis S, Kohlschutter A, Wanders RJ: Evidence for increased oxidative stress in peroxisomal D-bifunctional protein deficiency. Mol Genet Metab 2003, 79:281-287.
• [50]Pujol A, Hindelang C, Callizot N, Bartsch U, Schachner M, Mandel JL: Late onset neurological phenotype of the X-ALD gene inactivation in mice : a mouse model for adrenomyeloneuropathy. Hum Mol Genet 2002, 11:499-505.