Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy
Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy
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DOI：
10.1523/jneurosci.3094-18.2019
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发表时间：
2019-07-10
影响因子：
5.3
通讯作者：
Stegmueller, Judith
中科院分区：
文献类型：
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作者：
Joseph, Sabitha;Vingill, Siv;Stegmueller, Judith
轴突的髓鞘化促进电信号的快速传播和轴突的长期完整性。泛素-蛋白酶体系统对于适当的蛋白质稳态至关重要，这对于有丝分裂后细胞的相互作用尤其重要。在我们的研究中，我们研究了髓鞘细胞中表达的 E3 泛素连接酶 FBXO7-SCF（SKP1、Cul1、F-box 蛋白）如何影响轴突髓鞘单位。使用 Cnp1-Cre 驱动线删除小鼠少突胶质细胞和施万细胞中的 Fbxo7 会导致后肢麻痹导致运动障碍。它不会导致髓鞘细胞凋亡，也不会影响轴突的正常髓鞘形成或导致脱髓鞘。然而，它引发了中枢神经系统的轴突变性，并导致三七总神经系统轴突的严重变性，引发全面的神经病变。 CNS和PNS均表现出炎症，而PNS还表现为纤维化、巨噬细胞大量浸润和水肿。使用 Plp1-CreERT2 系髓鞘化后，他莫昔芬诱导的 Fbxo7 缺失导致少量轴突退化，从而导致非常轻微的周围神经病变。有趣的是，Fbxo7 的缺失也会导致雪旺细胞中的蛋白酶体活性降低，但小脑颗粒神经元中的蛋白酶体活性不会降低，这表明前一种细胞类型具有特定的敏感性。总之，我们的结果证明了 FBXO7 在髓鞘细胞中支持相关轴突的重要作用，这对于轴突-髓磷脂单元的正确发育建立和长期完整性至关重要。
Myelination of axons facilitates the rapid propagation of electrical signals and the long-term integrity of axons. The ubiquitin-proteasome system is essential for proper protein homeostasis, which is particularly crucial for interactions of postmitotic cells. In our study, we examined how the E3 ubiquitin ligase FBXO7-SCF (SKP1, Cul1, F-box protein) expressed in myelinating cells affects the axon-myelin unit. Deletion of Fbxo7 in oligodendrocytes and Schwann cells in mice using the Cnp1-Cre driver line led to motor impairment due to hindlimb paresis. It did not result in apoptosis of myelinating cells, nor did it affect the proper myelination of axons or lead to demyelination. It however triggered axonal degeneration in the CNS and resulted in the severe degeneration of axons in the PNS, inducing a full-blown neuropathy. Both the CNS and PNS displayed inflammation, while the PNS was also characterized by fibrosis, massive infiltration of macrophages, and edema. Tamoxifen-induced deletion of Fbxo7, after myelination using the Plp1-CreERT2 line, led to a small number of degenerated axons and hence a very mild peripheral neuropathy. Interestingly, loss of Fbxo7 also resulted in reduced proteasome activity in Schwann cells but not in cerebellar granule neurons, indicating a specific sensitivity of the former cell type. Together, our results demonstrate an essential role for FBXO7 in myelinating cells to support associated axons, which is fundamental to the proper developmental establishment and the long-term integrity of the axon-myelin unit.