HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage.
HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage.
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DOI：
10.1038/nn.2471
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发表时间：
2010-02
影响因子：
25
通讯作者：
Casaccia, Patrizia
中科院分区：
文献类型：
--
作者：
Kim, Jin Young;Shen, Siming;Dietz, Karen;He, Ye;Howell, Owain;Reynolds, Richard;Casaccia, Patrizia
组蛋白去乙酰化酶1（HDAC 1）是一种参与转录抑制的核酶。我们在此报告，在患有多发性硬化症的人类患者和患有铜酮诱导的脱髓鞘的小鼠、脱髓鞘的离体模型以及暴露于谷氨酸和TNF-α的培养神经元的脑中的受损轴突中检测到胞质HDAC 1。HDAC 1的核输出由与核受体CRM-1的相互作用介导，并导致线粒体转运受损。输出的HDAC 1和马达蛋白的驱动蛋白家族成员之间的复合物的形成阻碍了与货物分子的相互作用，从而抑制线粒体运动并诱导局部珠化。通过用来普霉素B抑制HDAC 1核输出、用HDAC活性的药理学抑制剂处理神经元或沉默HDAC 1而不是其他HDAC同种型来防止这种作用。这些数据共同确定HDAC 1的核输出是受损神经元中线粒体转运受损的关键事件。
Histone deacetylase 1 (HDAC1) is a nuclear enzyme involved in transcriptional repression. We report here that cytosolic HDAC1 is detected in damaged axons in brains of human patients with Multiple Sclerosis and of mice with cuprizone-induced demyelination, ex vivo models of demyelination and in cultured neurons exposed to glutamate and TNF-α. Nuclear export of HDAC1 is mediated by the interaction with the nuclear receptor CRM-1 and leads to impaired mitochondrial transport. The formation of complexes between exported HDAC1 and members of the kinesin family of motor proteins hinders the interaction with cargo molecules thereby inhibiting mitochondrial movement and inducing localized beadings. This effect is prevented by inhibiting HDAC1 nuclear export with leptomycin B, treating neurons with pharmacological inhibitors of HDAC activity or silencing HDAC1 but not other HDAC isoforms. Together these data identify nuclear export of HDAC1 as a critical event for impaired mitochondrial transport in damaged neurons.
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