Delayed Clinical and Pathological Signs in Twitcher (Globoid Cell Leukodystrophy) Mice on a C57BL/6 × CAST/Ei Background

Biswas, Sanjib; Biesiada, Homigol; Williams, Todd D.; Levine, Steven M.

doi:10.1006/nbdi.2002.0527

Cited by 14 publications

(7 citation statements)

References 55 publications

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“…This is likely because the new hybrid background derived from B6 ( twi colony) and B6C3 ( op colony) interacted with twi phenotypes. Altered longevity and clinical courses have been reported when the background of twi mice was altered (Duchen et al, 1980; Biswas et al, 2002; Tominaga et al, 2004; Rafi et al, 2005). …”

Section: Resultsmentioning

confidence: 99%

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Kondo

Adams²,

Vanier³

et al. 2011

J. Neurosci.

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Whether microglia and macrophages are beneficial or harmful in many neurological disorders including demyelinating diseases such as multiple sclerosis and the leukodystrophies is currently under debate. Answering this question is of special interest in globoid cell leukodystrophy (GLD), a genetic fatal demyelinating disease, because its rapidly progressive demyelination in the nervous system is accompanied by characteristic accumulation of numerous globoid macrophages. Therefore we cross-bred the twitcher (twi) mouse, a bona-fide model of GLD, with the macrophage-deficient osteopetrotic mutant and studied the resultant macrophage-deficient twitcher (twi+op) mouse. The twi+op mouse had few microglia and macrophages in the white matter and, interestingly, showed a more severe clinical phenotype compared to the twi mouse. The number of non-myelinated axons in the spinal cord was significantly higher in twi+op mice than in twi mice at 45 days old. The difference appeared to be due to impaired remyelination in twi+op mice, rather than accelerated demyelination. Quantitative reverse transcription PCR and immunohistochemical studies revealed that the recruitment of oligodendrocyte progenitor cells in response to demyelination was compromised in twi+op mice. Increased myelin debris in the white matter parenchyma of twi+op mice suggested that phagocytosis by macrophages may play an important role in promoting remyelination. Macrophage markers for both protective and destructive phenotypes were significantly upregulated in the spinal cord of twi mice, but were close to normal in twi+op mice due to the reduced macrophage number. The overall effects of macrophages in GLD appear to be beneficial to myelin by promoting myelin repair.

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Section: Resultsmentioning

confidence: 99%

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Kondo

Adams²,

Vanier³

et al. 2011

J. Neurosci.

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“…The saposin A and acid bgalactosidase genes are perfect examples of genetic factors, inasmuch as mutations in these genes can lead to a slowly progressive form of Krabbe disease in twitcher mice (72,73). Similarly, a change in the genetic background of twitcher mice, from C57BL/6 to C57BL/6 3 CAST/Ei background, significantly increases the life span (61.4 6 2.5 vs. 37.0 6 0.6 days), with fewer lectin-positive globoid cells, less gliosis, and a greater preservation of myelin, compared with C57BL/6 twitcher mice under moribund conditions, without any changes in the levels of psychosine, suggesting the involvement of a factor critical for the progression of Krabbe disease other than the accumulation of psychosine in the CNS (74). These observations raise a question as to whether the use of inhibitors of sPLA2, along with antiinflammatory drugs (e.g., NAC or statins), will protect against the loss of oligodendrocytes and thus increase the life span of twitcher mice or patients with Krabbe disease.…”

Section: Discussionmentioning

confidence: 97%

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Giri

Khan

Rattan

et al. 2006

Journal of Lipid Research

101

122

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Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside bgalactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose-and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.-Giri, S

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“…Scale bars ϭ 10 m. CE/J ϫ C57BL/6J mixed background had a milder course than did twitcher mice on the C57BL/6J background. More recently, Biswas et al (2002) described delayed clinical and pathologic signs in twitcher mice on the C57BL/6 ϫ CAST/Ei background. We found twitcher mice on the C57BL/6J-129SvEv mixed background had a more severe disease with a shorter lifespan, generalized seizures, massive neuronal cell death, most prominently in the CA3 area of hippocampus, and a significant accumulation of lactosylceramide in the brain.…”

Section: Discussionmentioning

confidence: 97%

Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the “twitcher” mouse model of globoid cell leukodystrophy

Tominaga

Matsuda

Kido

et al. 2004

J of Neuroscience Research

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The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.

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Delayed Clinical and Pathological Signs in Twitcher (Globoid Cell Leukodystrophy) Mice on a C57BL/6 × CAST/Ei Background

Cited by 14 publications

References 55 publications

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the “twitcher” mouse model of globoid cell leukodystrophy

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