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.
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Supported in part by the grants NS-24453, HE-03110 and ES-01104 from the National Institutes of Health, USPHS
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Taniike, M., Suzuki, K. Spacio-temporal progression of demyelination in twitcher mouse: with clinico-pathological correlation. Acta Neuropathol 88, 228–236 (1994). https://doi.org/10.1007/BF00293398
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DOI: https://doi.org/10.1007/BF00293398