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Free radical biology & medicine2016; 101; 261-271; doi: 10.1016/j.freeradbiomed.2016.10.009

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.
Copyright © 2016 Elsevier Inc. All rights reserved.
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Publication Date: 2016-10-15 PubMed ID: 27751910PubMed Central: PMC5154892DOI: 10.1016/j.freeradbiomed.2016.10.009Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study explores the molecular basis of equine neuroaxonal dystrophy (eNAD), a neurodegenerative disease in horses linked to low concentrations of α-tocopherol (α-TOH) – a form of Vitamin E. The research involved transcriptome profiling of the cervical spinal cord of affected horses and identified an upregulation of liver X receptor (LXR) target genes, potentially pointing towards a protective role for α-TOH in preventing neurodegeneration.

Research Context and Aim

  • This research focuses on equine neuroaxonal dystrophy (eNAD), a degenerative neurological disease in horses. eNAD has been associated with low levels of α-tocopherol (α-TOH), a variant of Vitamin E, in the serum and cerebrospinal fluid. This disease presents similar histological lesions to a human condition called ataxia, linked to mutations in the α-TOH transfer protein gene (TTPA). However, no TTPA mutations have been identified in eNAD, leaving its molecular basis unclear. The research sought to explore this unknown basis using transcriptome profiling of the cervical spinal cord in eNAD-affected horses.

Methodology and Results

  • The research leveraged global transcriptome sequencing of the cervical spinal cord in eNAD-affected horses. Analysis of differential gene expression resulted in identifying 157 significantly dysregulated transcripts within the spinal cord.
  • Statistical enrichment analysis pointed out a significant downregulation in specific pathways, including the ionotropic and metabotropic group III glutamate receptor pathways, synaptic vesicle trafficking, and cholesterol biosynthesis.
  • Gene co-expression analysis identified one gene module showing significant upregulation associated with eNAD. This module included liver X receptor (LXR) targets such as CYP7A1, APOE, PLTP, and ABCA1.

Validation and Hypothesis

  • Dysregulation of CYP7A1 and APOE was validated in an independent biological group, with CYP7A1 also found to be upregulated in the medulla oblongata of eNAD horses.
  • The evidence of LXR activation led researchers to hypothesize that tocopherols like α-TOH might modulate oxysterol-dependent LXR transcription factor activity, potentially providing a protective role. Specifically, they propose that α-TOH could prevent oxysterol accumulation and subsequent LXR activation to decrease lipid peroxidation-associated neurodegeneration.

Cite This Article

APA
Finno CJ, Bordbari MH, Valberg SJ, Lee D, Herron J, Hines K, Monsour T, Scott E, Bannasch DL, Mickelson J, Xu L. (2016). Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes. Free Radic Biol Med, 101, 261-271. https://doi.org/10.1016/j.freeradbiomed.2016.10.009

Publication

Free radical biology & medicine
ISSN: 1873-4596
NlmUniqueID: 8709159
Country: United States
Language: English
Volume: 101
Pages: 261-271
PII: S0891-5849(16)30452-X

Researcher Affiliations

Finno, Carrie J
  • 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, Matthew H
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
Valberg, Stephanie J
  • Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, United States.
Lee, David
  • Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
Herron, Josi
  • Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
Hines, Kelly
  • Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.
Monsour, Tamer
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
Scott, Erica
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
Bannasch, Danika L
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
Mickelson, James
  • Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States.
Xu, Libin
  • Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States.

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

Grant Funding

  • K01 OD015134 / NIH HHS
  • L40 TR001136 / NCATS NIH HHS
  • R00 HD073270 / NICHD NIH HHS
  • T32 ES007032 / NIEHS NIH HHS

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