白质营养不良
生物
共济失调
神经科学
小脑
肌张力障碍
背景(考古学)
病理
医学
古生物学
疾病
作者
Sunetra Sase,Akshata 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 Saleem Padiath,Erika L.F. Holzbaur,Steven S. Scherer,Adeline Vanderver
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2020-05-28
卷期号:9
被引量:16
摘要
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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