Loss of Branched O-Mannosyl Glycans in Astrocytes Accelerates Remyelination
Loss of Branched O-Mannosyl Glycans in Astrocytes Accelerates Remyelination
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DOI：
10.1523/jneurosci.3137-12.2013
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发表时间：
2013-06-12
影响因子：
5.3
通讯作者：
Taniguchi, Naoyuki
中科院分区：
文献类型：
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作者：
Kanekiyo, Kenji;Inamori, Kei-ichiro;Taniguchi, Naoyuki
在多发性硬化症等脱髓鞘疾病中，一个关键问题是重新髓鞘形成失败，这对保护轴突免受退化和恢复传导缺陷非常重要。然而，脱髓鞘/再髓鞘形成的潜在机制仍不清楚。N-乙酰氨基葡萄糖转移酶-IX(GnT-IX；又称GnT-VB)是一种脑特异性糖基转移酶，催化O-甘露糖基糖链结构的分支形成。α-肌营养不良聚糖的O-甘露糖化对于其作为细胞外基质受体的功能至关重要，但其分支结构的生物学意义尚不清楚，这些分支结构仅在大脑中发现。在本研究中，我们发现GnT-IX在体内形成了受体蛋白酪氨酸磷酸酶β(RPTPβ)上的支化O-甘露糖多聚糖。由于RPTPβ被认为在脱髓鞘疾病中起着调节作用，GnT-IX缺陷小鼠受到铜酮诱导的脱髓鞘。饲喂8周后，野生型小鼠脱髓鞘能力逐渐增强。在GnT-IX基因缺陷小鼠中，治疗4周后，痂体内髓鞘含量降低，但在8周时显著增加，提示GnT-IX基因缺陷促进了髓鞘再生。此外，GnT-IX基因缺陷小鼠痂体内星形胶质细胞的激活明显减弱，少突胶质细胞谱系分析表明，更多的少突胶质前体细胞分化为成熟的少突胶质细胞。综上所述，在铜酮诱导的脱髓鞘模型中，脑内胼胝体中的分支O-甘露糖聚糖是抑制再髓鞘形成的必要成分，这表明O-甘露糖聚糖的调节可能是治疗策略的候选。
In demyelinating diseases such as multiple sclerosis, a critical problem is failure of remyelination, which is important for protecting axons against degeneration and restoring conduction deficits. However, the underlying mechanism of demyelination/remyelination remains unclear. N-acetylglucosaminyltransferase-IX (GnT-IX; also known as GnT-Vb) is a brain-specific glycosyltransferase that catalyzes the branched formation of O-mannosyl glycan structures. O-Mannosylation of alpha-dystroglycan is critical for its function as an extracellular matrix receptor, but the biological significance of its branched structures, which are exclusively found in the brain, is unclear. In this study, we found that GnT-IX formed branched O-mannosyl glycans on receptor protein tyrosine phosphatase beta (RPTP beta) in vivo. Since RPTP beta is thought to play a regulatory role in demyelinating diseases, GnT-IX-deficient mice were subjected to cuprizone-induced demyelination. Cuprizone feeding for 8 weeks gradually promoted demyelination in wild-type mice. In GnT-IX-deficient mice, the myelin content in the corpus callosum was reduced after 4 weeks of treatment, but markedly increased at 8 weeks, suggesting enhanced remyelination under GnT-IX deficiency. Furthermore, astrocyte activation in the corpus callosum of GnT-IX-deficient mice was significantly attenuated, and an oligodendrocyte cell lineage analysis indicated that more oligodendrocyte precursor cells differentiated into mature oligodendrocytes. Together, branched O-mannosyl glycans in the corpus callosum in the brain are a necessary component of remyelination inhibition in the cuprizone-induced demyelination model, suggesting that modulation of O-mannosyl glycans is a likely candidate for therapeutic strategies.