Title: Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.
Authors: Finno, Carrie J; Bordbari, Matthew H; Valberg, Stephanie J; Lee, David; Herron, Josi; Hines, Kelly; Monsour, Tamer; Scott, Erica; Bannasch, Danika L; Mickelson, James; Xu, Libin
Published In Free Radic Biol Med, (2016 12)
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.
PubMed ID: 27751910
MeSH Terms: ATP Binding Cassette Transporter 1/genetics; ATP Binding Cassette Transporter 1/metabolism; Animals; Apolipoproteins E/genetics; Apolipoproteins E/metabolism; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cholesterol 7-alpha-Hydroxylase/genetics; Cholesterol 7-alpha-Hydroxylase/metabolism; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Horses; Liver X Receptors/genetics*; Liver X Receptors/metabolism; Male; Medulla Oblongata/metabolism; Medulla Oblongata/pathology; Molecular Sequence Annotation; Mutation; Neuroaxonal Dystrophies/genetics*; Neuroaxonal Dystrophies/metabolism; Neuroaxonal Dystrophies/pathology; Phospholipid Transfer Proteins/genetics; Phospholipid Transfer Proteins/metabolism; Protein Interaction Mapping; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, Ionotropic Glutamate/genetics; Receptors, Ionotropic Glutamate/metabolism; Receptors, Metabotropic Glutamate/genetics; Receptors, Metabotropic Glutamate/metabolism; Signal Transduction; Spinal Cord/metabolism; Spinal Cord/pathology; Transcription, Genetic*; Transcriptome*; Vitamin E Deficiency/genetics*; Vitamin E Deficiency/metabolism; Vitamin E Deficiency/pathology