Spacio-temporal progression of demyelination in twitcher mouse: with clinico-pathological correlation

Area of Science:

• Neuroscience
• Pathology
• Genetics

Background:

• Globoid cell leukodystrophy (GLD) is a lysosomal storage disorder caused by galactosylceramidase deficiency.
• The twitcher (twi/twi) mouse is a genetic model mirroring human GLD, exhibiting neurological decline and characteristic neuropathology.
• Understanding the temporal progression of neuropathology in the twitcher model is crucial for studying GLD.

Purpose of the Study:

• To investigate the spatiotemporal progression of neuropathology in the twitcher mouse model of GLD.
• To correlate the onset and severity of clinical symptoms with pathological changes.
• To elucidate the timing of demyelination relative to myelination across different neural tracts.

Main Methods:

• Longitudinal study of twitcher mice from postnatal day 10 to 45.
• Neuropathological assessment including identification of periodic acid-Schiff stain (PAS)-positive macrophages and myelin degeneration.
• Clinical evaluation of neurological symptoms such as tremor, spasticity, and cranial nerve dysfunction.

Main Results:

• No significant clinical or neuropathological changes were observed until postnatal day 15.
• Macrophage infiltration and myelin degeneration began around postnatal day 20 in the brain stem and cerebellar white matter, progressing to cerebral white matter by postnatal day 25, and gray matter by postnatal day 30.
• Severe demyelination was noted in the 8th and 5th cranial nerves, with neurological symptoms correlating strongly with pathological progression.
• Demyelination initiated 10–20 days post-myelination, suggesting uniform galactocerebroside metabolism across nerve tracts.
• Over-expression of glial fibrillary acidic protein preceded overt demyelination.

Conclusions:

• The twitcher mouse model exhibits a predictable spatiotemporal progression of neuropathology mirroring human GLD.
• The timing of demyelination relative to myelination suggests conserved metabolic processes in myelin maintenance across the murine brain.
• Early glial fibrillary acidic protein over-expression indicates a pre-symptomatic cellular response to the underlying pathology.