[en] Wilson's disease (WD) is caused by mutations in the copper transporting ATPase 7B (Atp7b). Patients present with liver pathology or behavioural disturbances. Studies on rodent models for WD so far mainly focussed on liver, not brain. The effect of knockout of atp7b on sensori-motor and cognitive behaviour, as well as neuronal number, inflammatory markers, copper and synaptic proteins in brain were studied in so-called toxic milk mice. Copper accumulated in striatum and hippocampus of toxic milk mice, but not in cerebral cortex. Inflammatory markers were increased in striatum and corpus callosum, but not in cerebral cortex and hippocampus, whereas neuronal numbers were unchanged. Toxic milk mice were mildly impaired in the rotarod and cylinder test and unable to acquire spatial memory in the Morris water maze. Despite the latter observation only synaptophysin of a number of synaptic proteins, was altered in the hippocampus of toxic milk mice. In addition to disturbances in neuronal signalling by increased brain copper, inflammation and inflammatory signalling from the periphery to the brain might add to the behavioural disturbances in the toxic milk mice. These mice can be used to evaluate therapeutic strategies to alleviate behavioural disturbances and cerebral pathology observed in WD.
Disciplines :
Neurologie
Auteur, co-auteur :
Terwel, Dick; Department of Neurology, Clinical Neurosciences, Bonn University, Bonn, Germany
Löschmann, Yi-Na; Department of Neurology, Clinical Neurosciences, Bonn University, 53127 Bonn, Germany
Schmidt, Hartmut H-J; Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
Schöler, Hans R; Max-Planck Institute of Molecular Biomedicine, Münster, Germany
Adlard P. A., Parncutt J. M., Finkelstein D. I., and, Bush A. I., (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease? J. Neurosci. 30, 1631-1636.
Allen K. J., Buck N. E., Cheah D. M., Gazeas S., Bhathal P., and, Mercer J. F., (2006) Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading. Biometals 19, 555-564. (Pubitemid 44291049)
Anzil A. P., Herrlinger H., Blinzinger K., and, Heldrich A., (1974) Ultrastructure of brain and nerve biopsy tissue in Wilson disease. Arch. Neurol. 31, 94-100.
Buiakova O. I., Xu J., Lutsenko S., Zeitlin S., Das K., Das S., Ross B. M., Mekios C., Scheinberg I. C. H., and, Gilliam T. C., (1999) Null mutation of the murine ATP7B (Wilson disease)gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum. Mol. Genet. 8, 1665-1671. (Pubitemid 29423875)
Bull P. C., Thomas G. R., Rommens J. M., Forbes J. R., and, Cox D. W., (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat. Genet. 5, 327-337. (Pubitemid 23351302)
Choi B. S., and, Zheng W., (2009) Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res. 1248, 14-21
Das S. K., and, Ray K., (2006) Wilson's disease: an update. Nat. Clin. Pract. Neurol. 2, 482-493. (Pubitemid 44275724)
D'Mello C., Le T., and, Swain M. G., (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor α signaling during peripheral organ inflammation. J. Neurosci. 29, 2089-2102.
Fujiwara N., Iso H., Kitanaka N., et al. (2006) Effects of copper metabolism on neurological functions in Wistar and Wilson's disease model rats. Biochem. Biophys. Res. Commun. 349, 1079-1086. (Pubitemid 44380206)
Goldschmith A., Infante C., Leiva J., Motles E., and, Palestini M., (2005) Interference of chronically ingested copper in long-term potentiation (LTP) of rat hippocampus. Brain Res. 1056, 176-182. (Pubitemid 41557705)
Holmes C., Cunningham C., Zotova E., Woolford J., Dean C., Kerr S., Culliford D., and, Perry V. H., (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768-774.
Hua Y., Schallert T., Keep R. F., Wu J., Hoff J. T., and, Xi G., (2002) Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33, 2478-2484.
Huster D., Finegold M. J., Morgan C. T., Burkhead J. C., Nixon R., Vanderwerf S. M., Gilliam C. T., and, Lutsenko S., (2006) Consequences of copper accumulation in the livers of the Atp7b(-/-) (Wilson disease gene) knockout mice. Am. J. Pathol. 168, 423-434. (Pubitemid 43271141)
Kawano H., Takeuchi Y., Yoshimoto K., Matsumoto K., and, Sugimoto T., (2001) Histological changes in monoaminergic neurons of Long-Evans Cinnamon rats. Brain Res. 915, 25-31. (Pubitemid 32907489)
Kim J. M., Ko S. B., Kwon S. J., Kim H. J., Han M. K., Kim D. W., Cho S. S., and, Jeon B. S., (2005) Ferrous and ferric iron accumulates in the brain of aged Long-Evans Cinnamon rats, an animal model of Wilson's disease. Neurosci. Lett. 382, 143-147. (Pubitemid 40725882)
Li Y., Togashi Y., Sato S., Emoto T., Kang J. H., Takeichi N., Kobayashi H., Kojima Y., Une Y., and, Uchino J., (1991) Spontaneous hepatic copper accumulation in Long-Evans Cinnamon rats with hereditary hepatitis. A model of Wilson's disease. J. Clin. Invest. 87, 1858-1861.
Madsen E., and, Gitlin J. D., (2007) Copper and iron disorders of the brain. Annu. Rev. Neurosci. 30, 317-337. (Pubitemid 47224759)
McGeer P. L., McGeer E. G., Itagaki S., and, Mizukawa K., (1987) Anatomy and pathology of the basal ganglia. Can. J. Neurol. Sci. 14 (3 Suppl), 363-372. (Pubitemid 17147617)
Michalczyk A. A., Rieger J., Allen K. J., Mercer J. F., and, Ackland M. L., (2000) Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation. Biochem. J. 352, 565-571. (Pubitemid 32011451)
Nagy Z. M., and, Misanin J. R., (1970) Visual perception in the retinal degenerate C3H mouse. J. Comp. Physiol. Psychol. 72, 306-310.
Nattkämper H., Halfter H., Khazaei M. R., Lohmann T., Gess B., Eisenacher M., Willscher E., and, Young P., (2009) Varying survival of motoneurons and activation of distinct molecular mechanism in response to altered peripheral myelin protein 22 gene dosage. J. Neurochem. 110, 935-946.
Roberts E. A., Robinson B. H., and, Yang S., (2008) Mitochondrial structure and function in the untreated Jackson toxic milk (tx-j) mouse, a model for Wilson disease. Mol. Genet. Metab. 93, 54-65. (Pubitemid 350236005)
Samuele A., Mangiagalli A., Armentero M. T., Fancellu R., Bazzini E., Vairetti M., Ferrigno A., Richelmi P., Nappi G., and, Blandini F., (2005) Oxidative stress and pro-apoptotic conditions in a rodent model of Wilson's disease. Biochim. Biophys. Acta 1741, 325-330. (Pubitemid 41338678)
Schallert T., Fleming S. M., Leasure J. L., Tillerson J. L., and, Bland S. T., (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacol. 39, 777-787. (Pubitemid 30103682)
Schindowski K., Bretteville A., Leroy K., Bégard S., Brion J. P., Hamdane M., and, Buée L., (2006) Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am. J. Pathol. 169, 599-616. (Pubitemid 44156317)
Theophilos M. B., Cox D. W., and, Mercer J. F., (1996) The toxic milk mouse is a murine model of Wilson disease. Hum. Mol. Genet. 5, 1619-1624. (Pubitemid 26328879)
Thomas G. R., Forbes J. R., Roberts E. A., Walshe J. M., and, Cox D. W., (1995) The Wilson disease gene: spectrum of mutations and their consequences. Nat. Genet. 9, 210-217.
Watanabe S., and, Yoshida M., (2007) Auditory cued spatial learning in mice. Physiol. Behav. 92, 906-910. (Pubitemid 350101681)
Weberpals M., Hermes M., Hermann S., Kummer M. P., Terwel D., Semmler A., Berger M., Schäfers M., and, Heneka M. T., (2009) NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J. Neurosci. 29, 14177-14184.
Weydt P., Hong S. Y., Kliot M., and, Möller T., (2003) Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport 14, 1051-1054. (Pubitemid 36829789)
Wu J., Forbes J. R., Chen H. S., and, Cox D. W., (1994) The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene. Nat. Genet. 7, 541-545. (Pubitemid 24308344)
