Defective glial maturation in vanishing white matter disease.
Defective glial maturation in vanishing white matter disease.
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DOI：
10.1097/nen.0b013e318203ae74
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发表时间：
2011-01
影响因子：
3.2
通讯作者：
van der Knaap MS
中科院分区：
文献类型：
--
作者：
Bugiani M;Boor I;van Kollenburg B;Postma N;Polder E;van Berkel C;van Kesteren RE;Windrem MS;Hol EM;Scheper GC;Goldman SA;van der Knaap MS
白质消失病 (VWM) 是一种与真核翻译起始因子 2B (eIF2B) 突变相关的遗传性白质脑病。这是一种婴儿、儿童和成人的疾病，他们会经历缓慢进行性的神经功能恶化，并因压力引发临床快速恶化，最终导致死亡。特征性神经病理学发现包括白质囊性变性，反应性胶质细胞增生稀少，星形胶质细胞变形，尽管少突胶质细胞密度增加，但髓鞘质缺乏。为了评估大胶质细胞成熟缺陷是否可能导致胶质细胞增生和髓鞘质缺乏，我们结合免疫细胞化学、组织化学、划伤试验、蛋白质印迹和定量 PCR，研究了 8 名 VWM 患者、4 名其他白质疾病患者和 6 名年龄匹配对照患者大脑中星形胶质细胞和少突胶质细胞的成熟状态。我们观察到 VWM 星形胶质细胞的增殖增加和成熟缺陷。它们显示出中间丝网络的异常组成，其中胶质原纤维酸性蛋白的 δ-亚型占主导地位，并且热休克蛋白 αB-晶状体蛋白增加，这支持了星形胶质细胞功能缺陷可能导致 VWM 中白质损失的可能性。我们还证明了 VWM 中髓鞘形成前少突胶质细胞祖细胞的数量显着增加，这可能解释了患者白质中少突胶质细胞增多和髓磷脂缺乏的共存。
Vanishing white matter disease (VWM) is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B (eIF2B). It is a disease of infants, children and adults, who experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathological findings include cystic degeneration of the white matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, we investigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other white matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot and quantitative PCR. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM. We also demonstrated a significant increase in numbers of pre-myelinating oligodendrocyte progenitors in VWM, which may explain the co-existence of oligodendrocytosis and myelin paucity in the patients’ white matter.