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Astroglial Redistribution of Aquaporin 4 During Spongy Degeneration in a Canavan Disease Mouse Model

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Abstract

Canavan disease is a spongiform leukodystrophy caused by an autosomal recessive mutation in the aspartoacylase gene. Deficiency of oligodendroglial aspartoacylase activity and a subsequent increase of its substrate N-acetylaspartate are the etiologic factors for the disease. N-acetylaspartate acts as a molecular water pump. Therefore, an osmotic–hydrostatic mechanism is thought to be involved in the development of the Canavan disease phenotype. Astrocytes express water transporters and are critically involved in regulating and maintaining water homeostasis in the brain. We used the ASPANur7/Nur7 mouse model of Canavan disease to investigate whether a disturbance of water homeostasis might be involved in the disease's progression. Animals showed an age-dependent impairment of motor performance and spongy degeneration in various brain regions, among the basal ganglia, brain stem, and cerebellar white matter. Astrocyte activation was prominent in regions which displayed less tissue damage, such as the corpus callosum, cortex, mesencephalon, and stratum Purkinje of cerebellar lobe IV. Immunohistochemistry revealed alterations in the cellular distribution of the water channel aquaporin 4 in astrocytes of ASPANur7/Nur7 mice. In control animals, aquaporin 4 was located exclusively in the astrocytic end feet. In contrast, in ASPANur7/Nur7 mice, aquaporin 4 was located throughout the cytoplasm. These results indicate that astroglial regulation of water homeostasis might be involved in the partial prevention of spongy degeneration. These observations highlight aquaporin 4 as a potential therapeutic target for Canavan disease.

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References

  • Acs P et al (2009) 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 57(8):807–814

    Article  PubMed  Google Scholar 

  • Amiry-Moghaddam M et al (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci U S A 100(4):2106–2111

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Arun P et al (2010) Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease. J Inherit Metab Dis 33(3):195–210

    Article  PubMed Central  PubMed  Google Scholar 

  • Assadi M et al (2010) Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease. Eur J Paediatr Neurol 14(4):354–359

    Article  PubMed  Google Scholar 

  • Badaut J et al (2002) Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 22(4):367–378

    Article  PubMed  CAS  Google Scholar 

  • Baslow MH (2002) Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 40(4):295–300

    Article  PubMed  CAS  Google Scholar 

  • Baslow MH (2003) Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci 21(3):185–190

    Article  PubMed  CAS  Google Scholar 

  • Baslow MH, Guilfoyle DN (2009) Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease? Neurochem Res 34(9):1523–1534

    Article  PubMed  CAS  Google Scholar 

  • Baslow MH et al (1999) Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes. J Mol Neurosci 13(1–2):47–53

    Article  PubMed  CAS  Google Scholar 

  • Baslow MH et al (2002) The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease-like rats. Neurochem Res 27(5):403–406

    Article  PubMed  CAS  Google Scholar 

  • Benarroch EE (2008) N-acetylaspartate and N-acetylaspartylglutamate: neurobiology and clinical significance. Neurology 70(16):1353–1357

    Article  PubMed  Google Scholar 

  • Brisevac D et al (2012) Regulation of ecto-5'-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors. Neurochem Int 61(5):681–688

    Article  PubMed  CAS  Google Scholar 

  • Carlson, G (2011) The use of four limb hanging wire tests to monitor muscle strength and condition over time. Treat-NMD Neuromuscular Network SOP

  • Chakraborty G et al (2001) Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78(4):736–745

    Article  PubMed  CAS  Google Scholar 

  • Clarner T et al (2011) Glial amyloid precursor protein expression is restricted to astrocytes in an experimental toxic model of multiple sclerosis. J Mol Neurosci 43(3):268–274

    Article  PubMed  CAS  Google Scholar 

  • Crawley JN (1999) Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 835(1):18–26

    Article  PubMed  CAS  Google Scholar 

  • Guadagno E, Moukhles H (2004) Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4.1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes. Glia 47(2):138–149

    Article  PubMed  Google Scholar 

  • Hemley SJ, et al (2013) Aquaporin-4 expression in posttraumatic syringomyelia. J Neurotrauma

  • Janson CG et al (2005) Lithium citrate for Canavan disease. Pediatr Neurol 33(4):235–243

    Article  PubMed  Google Scholar 

  • Kawai Y et al (2010) In vivo visualization of reactive gliosis using manganese-enhanced magnetic resonance imaging. Neuroimage 49(4):3122–3131

    Article  PubMed  Google Scholar 

  • Kim WR et al (2012) Regional difference of reactive astrogliosis following traumatic brain injury revealed by hGFAP-GFP transgenic mice. Neurosci Lett 513(2):155–159

    Article  PubMed  CAS  Google Scholar 

  • Kipp M et al (2011) Brain lipid binding protein (FABP7) as modulator of astrocyte function. Physiol Res 60(Suppl 1):S49–S60

    PubMed  CAS  Google Scholar 

  • Madhavarao CN et al (2005) Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease. Proc Natl Acad Sci U S A 102(14):5221–5226

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Manley GT et al (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6(2):159–163

    Article  PubMed  CAS  Google Scholar 

  • Maragakis NJ, Rothstein JD (2006) Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2(12):679–689

    Article  PubMed  CAS  Google Scholar 

  • Masaki H et al (2010) Immunocytochemical studies of aquaporin 4, Kir4.1, and alpha1-syntrophin in the astrocyte endfeet of mouse brain capillaries. Acta Histochem Cytochem 43(4):99–105

    Article  PubMed Central  PubMed  Google Scholar 

  • Matalon R, Michals-Matalon K (1993–2013) Canavan Disease. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K (eds) GeneReviews™ [Internet]. University of Washington, Seattle, Seattle, 1999 Sep 16 [updated 2011 Aug 11]

  • Moffett JR et al (1991) Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 2(3):131–134

    Article  PubMed  CAS  Google Scholar 

  • Moffett JR et al (2007) N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81(2):89–131

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Moffett JR et al (2011) Extensive aspartoacylase expression in the rat central nervous system. Glia 59(10):1414–1434

    Article  PubMed Central  PubMed  Google Scholar 

  • Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 129(4):905–913

    Article  PubMed  CAS  Google Scholar 

  • Nair A, Frederick TJ, Miller SD (2008) Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci 65(17):2702–2720

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Papadopoulos MC, Verkman AS (2007) Aquaporin-4 and brain edema. Pediatr Nephrol 22(6):778–784

    Article  PubMed  Google Scholar 

  • Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14(4):265–277

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434

    Article  PubMed  Google Scholar 

  • Potokar M et al (2013) Regulation of AQP4 surface expression via vesicle mobility in astrocytes. Glia 61(6):917–928

    Article  PubMed  Google Scholar 

  • Ren Z., et al (2013) 'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J Cereb Blood Flow Metab

  • Schmidt T et al (2013) Regional heterogeneity of cuprizone-induced demyelination: topographical aspects of the midline of the corpus callosum. J Mol Neurosci 49(1):80–88

    Article  PubMed  CAS  Google Scholar 

  • Seo HG et al (2010) Early motor balance and coordination training increased synaptophysin in subcortical regions of the ischemic rat brain. J Korean Med Sci 25(11):1638–1645

    Article  PubMed Central  PubMed  Google Scholar 

  • Solsona MD et al (2012) Lithium citrate as treatment of Canavan disease. Clin Neuropharmacol 35(3):150–151

    Article  PubMed  Google Scholar 

  • Steiner E et al (2012) Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia 60(11):1646–1659

    Article  PubMed  Google Scholar 

  • Traka M et al (2008) Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS. J Neurosci 28(45):11537–11549

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Helga Helten and Petra Ibold for excellent technical assistance. This study was supported by a START grant of the Medical Faculty (TC), RWTH Aachen, Germany.

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Authors and Affiliations

  1. Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Tim Clarner, Nicola Wieczorek, Barbara Krauspe, Katharina Jansen, Cordian Beyer & Markus Kipp

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  1. Tim Clarner
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  2. Nicola Wieczorek
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  3. Barbara Krauspe
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  4. Katharina Jansen
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  5. Cordian Beyer
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  6. Markus Kipp
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Correspondence to Tim Clarner.

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Tim Clarner and Nicola Wieczorek contributed equally to this work.

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Supplementary Fig. 1

Sequence analysis of WT, homozygote ASPANur7/Nur7 and heterozygote ASPANur7 animals is shown. Arrows mark the position of the mutation. Double peaks indicate a heterozygote genotype in which different DNA matrixes result in two distinct PCR-products. (JPEG 78 kb)

High resolution image (TIFF 559 kb)

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Clarner, T., Wieczorek, N., Krauspe, B. et al. Astroglial Redistribution of Aquaporin 4 During Spongy Degeneration in a Canavan Disease Mouse Model. J Mol Neurosci 53, 22–30 (2014). https://doi.org/10.1007/s12031-013-0184-4

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  • DOI: https://doi.org/10.1007/s12031-013-0184-4

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