An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice

Carrie J Finno, Matthew H. Bordbari, Giuliana Gianino, Brittni Ming-Whitfield, Erin Burns, Janel Merkel, Monica Britton, Blythe Durbin-Johnson, Erica A. Sloma, Marissa McMackin, Gino A Cortopassi, Victor Rivas, Marietta Barro, Cecilia K. Tran, Ingrid Gennity, Hadi Habib, Libin Xu, Birgit Puschner, Andrew D. Miller

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration.

Original languageEnglish (US)
Pages (from-to)289-302
Number of pages14
JournalFree Radical Biology and Medicine
Volume120
DOIs
StatePublished - May 20 2018

Keywords

  • RNA-sequencing
  • Transcription
  • Vitamin E

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Finno, C. J., Bordbari, M. H., Gianino, G., Ming-Whitfield, B., Burns, E., Merkel, J., Britton, M., Durbin-Johnson, B., Sloma, E. A., McMackin, M., Cortopassi, G. A., Rivas, V., Barro, M., Tran, C. K., Gennity, I., Habib, H., Xu, L., Puschner, B., & Miller, A. D. (2018). An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice. Free Radical Biology and Medicine, 120, 289-302. https://doi.org/10.1016/j.freeradbiomed.2018.02.037