TUBB4A的突变导致一系列脑白质营养不良,包括基底节和小脑萎缩(H-ABC),一种罕见的髓鞘过少的脑白质营养不良,通常与重复变异p.Asp249Asn(D249N)相关。我们开发了一种新颖的敲入小鼠模型,该模型具有杂合(Tubb4aD249N/)和纯合(Tubb4aD249N/D249N)突变,可概括震颤的进行性运动功能障碍,在H-ABC中看到的肌张力障碍和共济失调。Tubb4aD249N/D249N小鼠具有髓鞘形成缺陷以及成熟少突胶质细胞及其祖细胞的显著减少。此外,在Tubb4aD249N/D249N小鼠的小脑颗粒神经元和纹状体神经元中发生显著的损失。体外研究显示来自Tubb4aD249N/D249N小鼠的神经元的微管动力学的存活和功能障碍降低。因此,Tubb4aD249N/D249N小鼠证明了H-ABC的复杂细胞生理学,可能是由于对少突胶质细胞的独立作用,纹状体神经元,和小脑颗粒细胞在微管动力学改变的背景下,严重的神经发育缺陷。
在人类和其他动物细胞内,称为微管的细丝有助于支持细胞的形状,并将蛋白质移动到需要的位置。微管缺陷可能导致疾病。例如,影响称为TUBB4A的微管组件的基因突变在人类中引起一种罕见的脑部疾病,称为H-ABC。患有H-ABC的人表现出许多症状,包括异常行走,言语缺陷,吞咽受损,和几个认知缺陷。大脑几个区域的异常,包括小脑和纹状体导致了这些缺陷。.在这些结构中,在大脑及其支持细胞周围传递信息的神经元,被称为少突胶质细胞,死亡,这导致大脑的这些部分逐渐浪费掉。此时,没有可用于治疗H-ABC的疗法。此外,由于小鼠或其他实验动物缺乏合适的“模型”,对这种疾病的研究受到了阻碍。为了解决这个问题,Sase,Almad等人。产生的小鼠在编码人类蛋白质TUBB4A的小鼠等效基因中携带突变。实验表明,突变小鼠的身体症状与H-ABC的人类相似,包括异常的行走步态,协调能力差和不自主的运动,如抽搐和反射减少。H-ABC小鼠的小脑比正常小鼠小,这与H-ABC患者观察到的小脑消瘦是一致的。小鼠还失去了纹状体和小脑中的神经元,大脑和脊髓中的少突胶质细胞。此外,突变的TUBB4A蛋白影响H-ABC小鼠的行为和微管的形成。Sase的发现,Almad等人。提供了第一个具有人类H-ABC疾病许多特征的小鼠模型。该模型为研究该疾病和开发潜在的新疗法提供了有用的工具。
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.
Inside human and other animal cells, filaments known as microtubules help support the shape of the cell and move proteins to where they need to be. Defects in microtubules may lead to disease. For example, genetic mutations affecting a microtubule component called
TUBB4A cause a rare brain disease in humans known as H-ABC. Individuals with H-ABC display many symptoms including abnormal walking, speech defects, impaired swallowing, and several cognitive defects. Abnormalities in several areas of the brain, including the cerebellum and striatum contribute to these defects. . In these structures, the neurons that carry messages around the brain and their supporting cells, known as oligodendrocytes, die, which causes these parts of the brain to gradually waste away. At this time, there are no therapies available to treat H-ABC. Furthermore, research into the disease has been hampered by the lack of a suitable “model” in mice or other laboratory animals. To address this issue, Sase, Almad et al. generated mice carrying a mutation in a gene which codes for the mouse equivalent of the human protein
TUBB4A. Experiments showed that the mutant mice had similar physical symptoms to humans with H-ABC, including an abnormal walking gait, poor coordination and involuntary movements such as twitching and reduced reflexes. H-ABC mice had smaller cerebellums than normal mice, which was consistent with the wasting away of the cerebellum observed in individuals with H-ABC. The mice also lost neurons in the striatum and cerebellum, and oligodendrocytes in the brain and spinal cord. Furthermore, the mutant
TUBB4A protein affected the behavior and formation of microtubules in H-ABC mice. The findings of Sase, Almad et al. provide the first mouse model that shares many features of H-ABC disease in humans. This model provides a useful tool to study the disease and develop potential new therapies.