title: Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes.
abstract: The pathogenic drivers of sporadic and familial motor neuron disease (MND), such amyotrophic lateral sclerosis (ALS), are unknown. MND impairs the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology have remained elusive. The cytosolic and peripheral nucleoporin Ranbp2 is a crucial regulator of the Ran GTPase cycle and of the proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation ofRanbp2in mouse Thy1 motoneurons causes ALS syndromes with hypoactivity followed by hindlimb paralysis, respiratory distress and, ultimately, death. These phenotypes are accompanied by: a decline in the nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve; a reduction in the g-ratios of sciatic and phrenic nerves; and hypertrophy of motoneurons. Furthermore, 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 all undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation as a result of 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 downregulation of metalloproteinase 28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase 28 signaling, and proteostasis of substrates that are crucial to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes.
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kyoung-In
authors.initials: KI
authors.lastname: Cho
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Dosuk
authors.initials: D
authors.lastname: Yoon
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Sunny
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Danziger
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Grill
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA paulo.ferreira@duke.edu.|Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Paulo A
authors.identifier: 0000-0003-4585-1717
authors.initials: PA
authors.lastname: Ferreira
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology*; D009046:Motor Neurons / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000502:physiology*; D000074702:Proteostasis; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018925:Chemokines; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; C094493:ran-binding protein 2; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted
keywords: Amyotrophic lateral sclerosis; Chemokine signaling; Metalloproteinase; Motoneuron; Mouse gene knock-out; Nucleocytoplasmic transport; Proteostasis; Ran-binding protein 2; Transcriptomics