The progeroid gene BubR1 regulates axon myelination and motor function.
The progeroid gene BubR1 regulates axon myelination and motor function.
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DOI：
10.18632/aging.101032
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发表时间：
2016-09-12
期刊：
影响因子：
--
通讯作者：
Jang MH
中科院分区：
文献类型：
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作者：
Choi CI;Yoo KH;Hussaini SM;Jeon BT;Welby J;Gan H;Scarisbrick IA;Zhang Z;Baker DJ;van Deursen JM;Rodriguez M;Jang MH
髓鞘形成是少突胶质细胞在轴突周围形成髓鞘的过程，是中枢神经系统（CNS）中轴突信号转导和相关运动功能的关键。衰老的特征是髓鞘发生退行性变化，尽管正常和异常髓鞘形成的分子基础仍不完全清楚。在这里，我们报告了轴突髓鞘形成和相关的运动功能依赖于BubR 1，BubR 1是一种有丝分裂检查点蛋白，在低水平表达时与早老性表型有关，在过度表达时与健康寿命有关。我们发现，少突胶质细胞祖细胞增殖和少突胶质细胞密度显着减少突变小鼠与低量的BubR 1（BubR 1H/H小鼠），导致轴突髓鞘形成不足的大脑和脊髓。在这些组织中，必需的髓鞘相关基因如MBP和PLP 1的表达显著降低。与髓鞘形成缺陷一致，BubR 1H/H小鼠表现出各种运动缺陷，包括运动强度、协调和平衡受损，步态不规则和运动活动减少。总的来说，这些数据表明，BubR 1是少突胶质细胞生产和功能的关键决定因素，并提供了一个分子切入点，以了解年龄相关的轴突髓鞘形成的退行性变化。
Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/H mice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination, BubR1H/H mice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.