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  • 1
    Electronic Resource
    Electronic Resource
    Molecular Cloning and Expression of cDNA for Murine Galactocerebrosidase and Mutation Analysis of the Twitcher Mouse, a Model of Krabbe's Disease (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The cDNA for a murine galactocerebrosidase was isolated from a murine testis cDNA library on the basis of its homology with the cDNA for human galactocerebrosidase and a PCR method was used to clone the 5′ end. It has a 2,278-nucleotide sequence including a 2,004-nucleotide open reading frame, which encodes 668 amino acid residues. The identity between the human and murine amino acid sequences was very high, being calculated to be 84%. Sequencing of cDNA from liver of the twitcher mouse revealed a nonsense mutation at codon 339 (TGG → TGA). The most abundant mRNA of the murine galactocerebrosidase gave a 3.6-kb band, which was not detected in twitcher mice. This suggests that the cDNA (2,278 bp) we characterized represents a minor species generated by an alternate poly(A) signal and that most of the mRNA has a much longer 3′-untranslated region. Genome analysis revealed that this mutation was homozygous in the twitcher and heterozygous in the carrier but was not present in normal mice. The normal mouse cDNA but not the mutant cDNA of the galactocerebrosidase transfected into COS1 cells gave rise to an increase in enzymatic activity. We concluded that this mutation results in the deficiency of galactocerebrosidase in the twitcher mouse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66031118.x
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  • 2
    Electronic Resource
    Electronic Resource
    Spacio-temporal progression of demyelination in twitcher mouse: with clinico-pathological correlation (1994)
    Springer
    Acta neuropathologica 88 (1994), S. 228-236 
    Details
    ISSN: 1432-0533
    Keywords: Key words Globoid cell leukodystrophy ; Myelination ; Luxol fast blue-PAS ; Myelin basic protein ; Glial fibrillary acidic protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The twitcher (twi/twi) is an authentic murine model of human globoid cell leukodystrophy (GLD), caused by a deficiency of galactosylceramidase. Similar to human GLD, the twitcher shows progressive deterioration of neurological function and its neuropathology is characterized by a collection of periodic acid-Schift stain (PAS)-positive macrophages in the areas of demyelination. However, there are some differences in the clinico-pathological aspects between human and murine GLD. We investigated the spacio-temporal progression of neuropathology in the twitcher from postnatal day (PND) 10 to 45. No clinical symptoms or neuropathological changes were apparent in twi/twi until PND 15. Generally, infiltration of macrophages, concomitant with myelin degeneration, was recognized in the cerebellar white matter and the brain stem after PND 20, then in cerebral white matter after PND 25, and in cerebral and cerebellar gray matter after PND 30. The demyelination was very severe in the radix of the 8th and the 5th cranial nerves. The neurological symptoms such as tremor, spasticity and cranial nerve dysfunction were well correlated with the progression of pathological changes. Demyelination progressed in an orderly fashion such that myelin degeneration began 10 to 20 days after the commencement of myelination in any of the given nerve fiber tracts. This suggests that there are no significant differences in the metabolism of galactocerebroside in the myelin and myelin-forming cells in individual nerve fiber tracts throughout the murine brain. Over-expression of glial fibrillary acidic protein was already present before the initiation of obvious demyelination. In addition to the areas of demyelination, focal clustering of PAS-positive cells were seen in close association with neurons in the basal ganglia and hippocampus in this murine GLD twitcher, whereas in human GLD, PAS-positive cells tended to be limited within the white matter. Understanding of these orderly patterns of neuropathological features is of essential importance for evaluating the results of the forthcoming gene therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293398
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  • 3
    Electronic Resource
    Electronic Resource
    Spacio-temporal progression of demyelination in twitcher mouse: with clinico-pathological correlation (1994)
    Springer
    Acta neuropathologica 88 (1994), S. 228-236 
    Details
    ISSN: 1432-0533
    Keywords: Globoid cell leukodystrophy ; Myelination ; Luxol fast blue-PAS ; Myelin basic protein Glial fibrillary acidic protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The twitcher (twi/twi) is an authentic murine model of human globoid cell leukodystrophy (GLD), caused by a deficiency of galactosylceramidase. Similar to human GLD, the twitcher shows progressive deterioration of neurological function and its neuropathology is characterized by a collection of periodic acid-Schift stain (PAS)-positive macrophages in the areas of demyelination. However, there are some differences in the clinico-pathological aspects between human and murine GLD. We investigated the spacio-temporal progression of neuropathology in twitcher from postnatal day (PND) 10 to 45. No clinical symptoms or neuropathological changes were apparent in twi/twi until PND 15. Generally, infiltration of macrophages, concomitant with myelin degeneration, was recognized in the cerebellar white matter and the brain stem after PND 20, then in cerebral white matter after PND 25, and in cerebral and cerebellar gray matter after PND 30. The demyelination was very severe in the radix of the 8th and the 5th cranial nerves. The neurological symptoms such as tremor, spasticity and cranial nerve dysfunction were well correlated with the progression of pathological changes. Demyelination progressed in an orderly fashion such that myelin degeneration began 10 to 20 days after the commencement of myelination in any of the given nerve fiber tracts. This suggests that there are no significant differences in the metabolism of galactocerebroside in the myelin and myelin-forming cells in individual nerve fiber tracts throughout the murine brain. Over-expression of glial fibrillary acidic protein was already present before the initiation of obvious demyelination. In addition to the areas of demyelination, focal clustering of PAS-positive cells were seen in close association with neurons in the basal ganglia and hippocampus in this murine GLD twitcher, whereas in human GLD, PAS-positive cells tended to be limited within the white matter. Understanding of these orderly patterns of neuropathological features is of essential importance for evaluating the results of the forthcoming gene therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293398
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  • 4
    Electronic Resource
    Electronic Resource
    Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease (1995)
    Springer
    Acta neuropathologica 89 (1995), S. 296-304 
    Details
    ISSN: 1432-0533
    Keywords: Key words GM2 gangliosidosis ; GM2 ganglioside ; β Hexosaminidase A ; Gene targeting ; Membranous ; cytoplasmic bodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of α-hexosaminidase A. The mice were completely devoid of β-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, wer e identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM2 ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00309622
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  • 5
    Electronic Resource
    Electronic Resource
    Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease (1995)
    Springer
    Acta neuropathologica 89 (1995), S. 296-304 
    Details
    ISSN: 1432-0533
    Keywords: GM2 gangliosidosis ; GM2 ganglioside ; β Hexosaminidase A ; Gene targeting ; Membranous cytoplasmic bodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of α-hexosaminidase A. The mice were completely devoid of β-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, were identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM2 ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00309622
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    Paper (German National Licenses)
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  • 6
    Electronic Resource
    Electronic Resource
    Murine model of genetic demyelinating disease: The twitcher mouse (1995)
    New York, NY [u.a.] : Wiley-Blackwell
    Microscopy Research and Technique 32 (1995), S. 204-214 
    Details
    ISSN: 1059-910X
    Keywords: Central and peripheral nervous systems ; Demyelination ; Remyelination ; Oligodendrocytes ; Schwann cells ; Globoid cell leukodystrophy ; Krabbe disease ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Natural Sciences in General
    Notes: Twitcher mouse is an authentic murine model of human genetic demyelinating disease, globoid cell leukodystrophy (GLD), or Krabbe disease. Since its discovery at the Jackson Laboratory (Bar Harbor, ME) this model has been used extensively for the morphological, biochemical-enzymatic studies to clarify pathogenesis and also for therapeutic manipulation of genetic demyelinating disease in humans. As a result of these studies, now we know that (1) GLD is caused by a deficiency of lysosomal enzyme galactosylceramidase, and a toxic metabolite, psychosine, accumulates in the tissue, including the nervous system, damaging myelin forming cells and resulting in secondary demyelination; (2) morphological features of demyelination and associated cellular reactions in demyelination in this mutant are similar to those seen in autoimmune or toxic demyelination; and (3) with enzyme supplementation provided by bone marrow transplantation, remyelination occurs to some extent in demyelinated fibers in both central and peripheral nervous systems of twitcher mouse. © 1995 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jemt.1070320304
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