title: Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.
abstract: Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential gene expression analysis identified 157 significantly (FDR<0.05) dysregulated transcripts within the spinal cord of eNAD-affected horses. Statistical enrichment analysis identified significant downregulation of the ionotropic and metabotropic group III glutamate receptor, synaptic vesicle trafficking and cholesterol biosynthesis pathways. Gene co-expression analysis identified one module of upregulated genes significantly associated with the eNAD phenotype that included the liver X receptor (LXR) targets CYP7A1, APOE, PLTP and ABCA1. Validation of CYP7A1 and APOE dysregulation was performed in an independent biologic group and CYP7A1 was found to be additionally upregulated in the medulla oblongata of eNAD horses. Evidence of LXR activation supports a role for modulation of oxysterol-dependent LXR transcription factor activity by tocopherols. We hypothesize that the protective role of α-TOH in eNAD may reside in its ability to prevent oxysterol accumulation and subsequent activation of the LXR in order to decrease lipid peroxidation associated neurodegeneration.
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: cjfinno@ucdavis.edu.
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Finno
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Bordbari
authors.affiliation: Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, United States.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Valberg
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
authors.forename: David
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
authors.forename: Josi
authors.initials: J
authors.lastname: Herron
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hines
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
authors.forename: Tamer
authors.initials: T
authors.lastname: Monsour
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
authors.forename: Erica
authors.initials: E
authors.lastname: Scott
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
authors.forename: Danika L
authors.initials: DL
authors.lastname: Bannasch
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States.
authors.forename: James
authors.initials: J
authors.lastname: Mickelson
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
authors.forename: Libin
authors.initials: L
authors.lastname: Xu
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D006736:Horses; D000071518:Liver X Receptors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism / Q000473:pathology; D058977:Molecular Sequence Annotation; D009154:Mutation; D019150:Neuroaxonal Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058468:Receptors, Ionotropic Glutamate / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D059467:Transcriptome; D014811:Vitamin E Deficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002352:Carrier Proteins; D000071518:Liver X Receptors; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; D058468:Receptors, Ionotropic Glutamate; D018094:Receptors, Metabotropic Glutamate; C017763:alpha-tocopherol transfer protein; D002790:Cholesterol 7-alpha-Hydroxylase
keywords: Cholesterol; RNA-sequencing; Vitamin E