Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy

Abstract

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.SIGNIFICANCE STATEMENT The myelination of axons facilitates the fast propagation of electrical signals and the trophic support of the myelin-axon unit. Here, we report that deletion of Fbxo7 in myelinating cells in mice triggered motor impairment but had no effect on myelin biogenesis. Loss of Fbxo7 in myelinating glia, however, led to axonal degeneration in the CNS and peripheral neuropathy of the axonal type. In addition, we found that Schwann cells were particularly sensitive to Fbxo7 deficiency reflected by reduced proteasome activity. Based on these findings, we conclude that Fbxo7 is essential for the support of the axon-myelin unit and long-term axonal health.