TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
Open Access
- 28 May 2020
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
Abstract
Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.Keywords
Funding Information
- The Commonwealth Universal Research Enhancement (RFA 67-54)
- National Institutes of Health (R35 GM126950)
- National Institutes of Health (R37 NS060698)
- German Research Foundation (Fellowship BO 5434/1-1))
- National Institutes of Health (R33NS104384)
- National Institutes of Health (R33NS106087)
- National Institutes of Health (R01NS095884)
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