title: Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22.
abstract: Unique deficits in the function of adult sensory neurons as part of their early neurodegeneration might account for progressive polyneuropathy during chronic diabetes mellitus. Here, we provide structural and functional evidence for aberrant pre-mRNA splicing in a chronic type 1 model of experimental diabetic polyneuropathy (DPN). Cajal bodies (CBs), unique nuclear substructures involved in RNA splicing, increased in number in diabetic sensory neurons, but their expected colocalization with survival motor neuron (SMN) proteins was reduced - a mislocalization described in motor neurons of spinal muscular atrophy. Small nuclear ribonucleoprotein particles (snRNPs), also participants in the spliceosome, had abnormal multiple nuclear foci unassociated with CBs, and their associated snRNAs were reduced. CWC22, a key spliceosome protein, was aberrantly upregulated in diabetic dorsal root ganglia (DRG), and impaired neuronal function. CWC22 attenuated sensory neuron plasticity, with knockdownin vitroenhancing their neurite outgrowth. Further, axonal delivery of CWC22 siRNA unilaterally to locally knock down the aberrant protein in diabetic nerves improved aspects of sensory function in diabetic mice. Collectively, our findings identify subtle but significant alterations in spliceosome structure and function, including dysregulated CBs and CWC22 overexpression, in diabetic sensory neurons that offer new ideas regarding diabetic sensory neurodegeneration in polyneuropathy.
authors.affiliation: Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada, T6G 2G3.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada, T6G 2G3.
authors.forename: Ambika
authors.initials: A
authors.lastname: Chandrasekhar
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1.
authors.forename: Chu
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1.
authors.forename: Hilarie
authors.initials: H
authors.lastname: Ng
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1.
authors.forename: Cristiane
authors.initials: C
authors.lastname: de la Hoz
authors.affiliation: Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada, T6G 2G3 zochodne@ualberta.ca.|Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1.
authors.forename: Douglas W
authors.identifier: 0000-0003-1692-5983
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000818:Animals; D001284:Atrophy; D002467:Cell Nucleus / Q000378:metabolism*; D020541:Coiled Bodies / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D009431:Neural Conduction; D000071446:Neuronal Outgrowth; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012342:RNA, Small Nuclear / Q000378:metabolism; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D055532:SMN Complex Proteins / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D017381:Spliceosomes / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C000607845:CWC22 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012342:RNA, Small Nuclear; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins
keywords: Diabetic polyneuropathy; Gemini of coiled bodies; SMN complex proteins; Sensory ganglia; Small nuclear ribonucleoproteins