The pathogenic drivers of sporadic and familial motor neuron disease (MND), such ALS, are unknown. MND impair the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology are heretofore elusive. The cytosolic and peripheral nucleoporin, Ranbp2, is a critical regulator of the Ran GTPase cycle and proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation of Ranbp2 in mouse Thy1-motoneurons causes ALS syndromes with hypoactivity followed by hind limb paralysis, respiratory distress and ultimately, death. These phenotypes are accompanied by declines of nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve, g-ratios of sciatic and phrenic nerves, and hypertrophy of motoneurons. Further, Ranbp2 loss disrupts the nucleocytoplasmic partitioning of the import and export nuclear receptors, importin-β and exportin-1, respectively, Ran GTPase and histone deacetylase-4. Whole-transcriptome, proteomic and cellular analyses uncovered that the chemokine receptor, Cxcr4, its antagonizing ligands, Cxcl12 and Cxcl14, and effector, latent and activated Stat3, undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation, by Ranbp2 loss in motoneurons. These effects were accompanied by paracrine and autocrine neuroglial deregulation of hnRNPH3 proteostasis in sciatic nerve and motoneurons, respectively, and post-transcriptional down-regulation of metalloproteinase-28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase-28 signaling and proteostasis of substrates critical to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes.
- Received September 8, 2016.
- Accepted December 12, 2016.
- © 2017. Published by The Company of Biologists Ltd
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