Increased apoptosis and hypomyelination in cerebral white matter of macular mutant mouse brain.
Increased apoptosis and hypomyelination in cerebral white matter of macular mutant mouse brain.
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DOI：
10.1016/j.ymgmr.2015.05.005
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发表时间：
2015-09
影响因子：
1.9
通讯作者：
Maruo Y
中科院分区：
文献类型：
--
作者：
Takikita S;Takano T;Narita T;Maruo Y
发育中的大脑髓鞘形成不足通常伴有先天性代谢障碍。Menkes扭结毛发病是一种X连锁的铜转运受损的神经退行性疾病，由Menkes病基因（跨膜铜转运p型ATP酶基因（ATP 7A））突变引起。在黄斑突变小鼠模型中，Menkes基因（斑驳基因）的鼠直系同源物发生突变，观察到广泛的神经变性和随后的死亡。虽然已经报道了黄斑小鼠髓鞘蛋白的一些生化分析，但目前缺乏这种小鼠模型中髓鞘形成的详细组织学研究。由于髓鞘异常是人类Menkes病的神经病理学表现之一，在这项研究中，通过免疫组织化学评价了黄斑小鼠脑中的早期髓鞘形成。用4%多聚甲醛灌注两周龄黄斑小鼠和正常同窝小鼠。石蜡包埋和振动切片的免疫组织化学染色进行使用的抗体对CN-β，裂解的半胱天冬酶-3或O 4（标记的未成熟少突胶质细胞）。这种染色显示黄斑小鼠的脑髓鞘形成通常发育不良，并且内囊、胼胝体和扣带皮质中的髓鞘形成不足是显著的。此外，在胼胝体和内囊中观察到裂解的caspase-3阳性细胞数量增加。据报道，低铜饮食诱导的铜缺乏可诱导少突胶质细胞功能障碍，并导致该小鼠模型中的髓鞘形成不足。总之，本研究中在Menkes病小鼠模型中观察到的髓鞘形成不足被认为是由发育中大脑中未成熟少突胶质细胞的凋亡增加通过细胞内铜代谢不足诱导的。
Hypomyelination in developing brain is often accompanied by congenital metabolic disorders. Menkes kinky hair disease is an X-linked neurodegenerative disease of impaired copper transport, resulting from a mutation of the Menkes disease gene, a transmembrane copper-transporting p-type ATPase gene (ATP7A). In a macular mutant mouse model, the murine ortholog of Menkes gene (mottled gene) is mutated, and widespread neurodegeneration and subsequent death are observed. Although some biochemical analysis of myelin protein in macular mouse has been reported, detailed histological study of myelination in this mouse model is currently lacking. Since myelin abnormality is one of the neuropathologic findings of human Menkes disease, in this study early myelination in macular mouse brain was evaluated by immunohistochemistry. Two-week-old macular mice and normal littermates were perfused with 4% paraformaldehyde. Immunohistochemical staining of paraffin embedded and vibratome sections was performed using antibodies against either CNPase, cleaved caspase-3 or O4 (marker of immature oligodendrocytes). This staining showed that cerebral myelination in macular mouse was generally hypoplastic and that hypomyelination was remarkable in internal capsule, corpus callosum, and cingulate cortex. In addition, an increased number of cleaved caspase-3 positive cells were observed in corpus callosum and internal capsule. Copper deficiency induced by low copper diet has been reported to induce oligodendrocyte dysfunction and leads to hypomyelination in this mouse model. Taken together, hypomyelination observed in this study in a mouse model of Menkes disease is assumed to be induced by increased apoptosis of immature oligodendrocytes in developing cerebrum, through deficient intracellular copper metabolism.