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An In Vitro Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy
Published on: October 21, 2014
Macrophages counteract demyelination in a mouse model of globoid cell leukodystrophy
Yoichi Kondo1, Jessica M Adams, Marie T Vanier
1Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. kondoy@svm.vetmed.wisc.edu
Abstract:
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 a 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 nonmyelinated axons in the spinal cord was significantly higher in twi+op mice than in twi mice at 45 d 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.
Insights
In globoid cell leukodystrophy (GLD), macrophages are beneficial for myelin repair. Reducing macrophages worsened the disease, indicating their protective role in this demyelinating disorder.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- The role of microglia and macrophages in neurological disorders, particularly demyelinating diseases like multiple sclerosis and leukodystrophies, is debated.
- Globoid cell leukodystrophy (GLD) is a fatal genetic demyelinating disease characterized by significant globoid macrophage accumulation.
Purpose of the Study:
- To investigate the role of macrophages in globoid cell leukodystrophy (GLD) by creating a macrophage-deficient mouse model.
- To determine whether macrophages are beneficial or detrimental to myelin repair in GLD.
Main Methods:
- Cross-breeding the twitcher (twi) mouse model of GLD with a macrophage-deficient osteopetrotic (op) mutant to create the macrophage-deficient twi+op mouse.
- Analyzing white matter, clinical phenotype, axon counts, remyelination, oligodendrocyte progenitor cell recruitment, and myelin debris in twi and twi+op mice.
- Utilizing quantitative reverse transcription PCR and immunohistochemical studies to assess gene expression and protein markers.
Main Results:
- Macrophage-deficient twi+op mice exhibited fewer microglia and macrophages, a more severe clinical phenotype, and a higher number of nonmyelinated axons compared to twi mice.
- Impaired remyelination, rather than accelerated demyelination, was observed in twi+op mice.
- Oligodendrocyte progenitor cell recruitment was compromised, and myelin debris accumulation increased in twi+op mice, suggesting a crucial role for macrophage phagocytosis in remyelination.
- Macrophage markers associated with both protective and destructive phenotypes were upregulated in twi mice but near normal in twi+op mice.
Conclusions:
- Macrophages play a beneficial role in globoid cell leukodystrophy (GLD) by promoting myelin repair.
- The presence of macrophages aids in the recruitment of oligodendrocyte progenitor cells and the clearance of myelin debris, facilitating remyelination.
- Targeting macrophages could be a therapeutic strategy for enhancing myelin repair in GLD.
