Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration
Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration
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DOI：
10.1093/hmg/dds179
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发表时间：
2012-08-15
影响因子：
3.5
通讯作者：
Meisler, Miriam H.
中科院分区：
文献类型：
--
作者：
Ferguson, C. J.;Lenk, G. M.;Meisler, Miriam H.
FIG4是一种普遍表达的磷酸酶，与FAB1/PIKFYVE和VAC14复合，调节信号脂质PI(3,5)P-2的生物合成。Fig4在小鼠中的零突变导致大脑和周围神经节的海绵状变性，髓鞘形成缺陷和少年死亡。人类FIG4的部分功能丧失导致严重形式的CharcotMarieTooth神经病变。来自空白小鼠的神经元含有来自核内体/溶酶体途径的增大的空泡，星形胶质细胞积累参与自噬的蛋白质。其他细胞缺陷包括星形胶质细胞增生和小胶质细胞增生。为了区分神经元和胶质对Fig4缺失小鼠海绵状变性的贡献，我们在神经元特异性烯醇化酶启动子和星形胶质细胞特异性胶质纤维酸性蛋白启动子的控制下，在转基因小鼠中表达Fig4。图4的神经元表达足以挽救细胞和神经表型，包括海绵状变性、胶质瘤和少年致死。相反，在星形胶质细胞中表达Fig4可以阻止自噬标记物的积累和小胶质细胞形成，但不能阻止海绵状变性或致死性。为了确认海海绵样变性的神经元起源，我们生成了图4的一个带束的等位基因，并将其与表达神经元特异性突触蛋白启动子的Cre重组酶的小鼠杂交。神经元中Fig4条件性失活的小鼠出现海绵状变性和全谱神经异常。数据表明，Fig4在神经元中的表达是防止海绵状变性的必要和充分条件。因此，对FIG4缺陷患者的治疗需要纠正神经元缺陷。
FIG4 is a ubiquitously expressed phosphatase that, in complex with FAB1/PIKFYVE and VAC14, regulates the biosynthesis of the signaling lipid PI(3,5)P-2. Null mutation of Fig4 in the mouse results in spongiform degeneration of brain and peripheral ganglia, defective myelination and juvenile lethality. Partial loss-of-function of human FIG4 results in a severe form of CharcotMarieTooth neuropathy. Neurons from null mice contain enlarged vacuoles derived from the endosome/lysosome pathway, and astrocytes accumulate proteins involved in autophagy. Other cellular defects include astrogliosis and microgliosis. To distinguish the contributions of neurons and glia to spongiform degeneration in the Fig4 null mouse, we expressed Fig4 under the control of the neuron-specific enolase promoter and the astrocyte-specific glial fibrillary acidic protein promoter in transgenic mice. Neuronal expression of Fig4 was sufficient to rescue cellular and neurological phenotypes including spongiform degeneration, gliosis and juvenile lethality. In contrast, expression of Fig4 in astrocytes prevented accumulation of autophagy markers and microgliosis but did not prevent spongiform degeneration or lethality. To confirm the neuronal origin of spongiform degeneration, we generated a floxed allele of Fig4 and crossed it with mice expressing the Cre recombinase from the neuron-specific synapsin promoter. Mice with conditional inactivation of Fig4 in neurons developed spongiform degeneration and the full spectrum of neurological abnormalities. The data demonstrate that expression of Fig4 in neurons is necessary and sufficient to prevent spongiform degeneration. Therapy for patients with FIG4 deficiency will therefore require correction of the deficiency in neurons.