<i>TUBB4A</i> mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model.

Abstract

Mutations in <i>TUBB4A</i> 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 (<i>Tubb4a^D249N/+</i>) and the homozygous (<i>Tubb4a^D249N/D249N</i>) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. <i>Tubb4a^D249N/D249N</i> 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 <i>Tubb4a^D249N/D249N</i> mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from <i>Tubb4a^D249N/D249N</i> mice. Thus <i>Tubb4a^D249N/D249N</i> 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.