NDLI: Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	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
Description	Author Affiliation: Finno CJ ( Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: cjfinno@ucdavis.edu.); Bordbari MH ( Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.); Valberg SJ ( Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, United States.); Lee D ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.); Herron J ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.); Hines K ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.); Monsour T ( Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.); Scott E ( Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.); Bannasch DL ( Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.); Mickelson J ( Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States.); Xu L ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.)
Abstract	Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid -tocopherol ( -TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the -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 -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.
File Format	HTM / HTML
ISSN	08915849
Journal	Free Radical Biology and Medicine
Volume Number	101
e-ISSN	18734596
Language	English
Publisher	Elsevier
Publisher Date	2016-12-01
Publisher Place	United States
Access Restriction	One Nation One Subscription (ONOS)
Content Type	Text
Resource Type	Article
Subject	Physiology (medical) Biochemistry

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