TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
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DOI：
10.7554/elife.52986
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发表时间：
2020-05-28
期刊：
影响因子：
7.7
通讯作者：
Vanderver, Adeline
中科院分区：
文献类型：
--
作者：
Sase, Sunetra;Almed, Akshata A.;Vanderver, Adeline
TUBB4A 突变会导致一系列脑白质营养不良，包括髓鞘形成低下伴基底神经节和小脑萎缩 (H-ABC)，这是一种罕见的髓鞘形成低下性脑白质营养不良，通常与反复出现的变异 p.Asp249Asn (D249N) 相关。我们开发了一种新型敲入小鼠模型，其中包含杂合子（Tubb4a（D249N / +））和纯合子（Tubb4a（D249N / D249N））突变，概括了H-ABC中出现的进行性运动功能障碍，包括震颤、肌张力障碍和共济失调。 Tubb4a(D249N/D249N) 小鼠存在髓鞘形成缺陷，并且成熟少突胶质细胞及其祖细胞急剧减少。此外，Tubb4a(D249N/D249N) 小鼠的小脑颗粒神经元和纹状体神经元发生显着损失。体外研究表明 Tubb4a(D249N/D249N) 小鼠神经元的存活率下降和微管动力学功能障碍。因此，Tubb4a(D249N/D249N)小鼠表现出H-ABC复杂的细胞生理学，可能是由于在微管动力学改变的背景下对少突胶质细胞、纹状体神经元和小脑颗粒细胞的独立影响，并具有严重的神经发育缺陷。
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 (Tubb4a(D249N/+)) and the homozygous (Tubb4a(D249N/D249N)) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4a(D249N/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 Tubb4a(D249N/D249N) mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4a(D249N/D249N) mice. Thus Tubb4a(D249N/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.