eLife (May 2020)

TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model

  • Sunetra Sase,
  • Akshata A Almad,
  • C Alexander Boecker,
  • Pedro Guedes-Dias,
  • Jian J Li,
  • Asako Takanohashi,
  • Akshilkumar Patel,
  • Tara McCaffrey,
  • Heta Patel,
  • Divya Sirdeshpande,
  • Julian Curiel,
  • Judy Shih-Hwa Liu,
  • Quasar Padiath,
  • Erika LF Holzbaur,
  • Steven S Scherer,
  • Adeline Vanderver

DOI
https://doi.org/10.7554/eLife.52986
Journal volume & issue
Vol. 9

Abstract

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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.

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