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

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.

Lipid peroxidation biomarkers for evaluating oxidative stress in equine neuroaxonal dystrophy

“…A similar phenomenon was observed by our group in mice deficient in tocopherol (alpha) transfer protein ( Ttpa –/– ). These mice develop a postnatal sensory neurodegeneration like that observed in eNAD/EDM . In wild‐type mice, concentrations of 24(S)‐hydroxycholesterol significantly increase in the SC tissue with age, suggesting adequate CYP46A1 activity.…”

“…24‐Ketocholesterol was significantly decreased in the SC tissues of eNAD/EDM affected horses. Although a negative correlation was observed with age and 24‐ketocholesterol, similar to reports in other species, no significant difference in age was found between diseased and healthy groups. 24‐ketocholesterol is produced by CYP46A1 from desmosterol (Figure ) .…”

Genome-Wide Association Study and Subsequent Exclusion of ATCAY as a Candidate Gene Involved in Equine Neuroaxonal Dystrophy Using Two Animal Models

“…Once recapitulated, a subset of breeding pairs was placed on a vitE supplemented diet (vitE+++ = 600 mg of dl-α-tocopheryl acetate/kg feed) at introduction of the male and maintained on this diet throughout gestation and lactation. This diet has been previously demonstrated to prevent the ataxic phenotype in tocopherol-transfer protein-null mice [32]. Once weaned, these mice were maintained on the vitE+++ diet until terminal use at one or two months of age.…”

“…As the Atcay ji-hes phenotype can be visually determined [17], we evaluated methods to quantify the obvious gait abnormalities. Balance beam, TreadScan [18,34], and horizontal ladder beam [19,32] tests were used to measure balance and coordination of movement. The Atcay hes/hes mice were unable to complete any portion of the balance beam test due to their severe ataxic and dystonic phenotype.…”

Vitamin E: Regulatory role on gene and protein expression and metabolomics profiles

“…Studies that investigated the effects of vitamin E deficiency or supplementation using transcriptome analyses are limited ( Table 3). Vitamin E deficiency has been shown to upregulate the liver X receptor in the spinal cords of Ttpa-null mice and equine neuroaxonal dystrophy horses (33,34). The transcriptome analysis of mammary tumors induced by estrogen showed that δand γ-tocopherols were effective in reducing mammary tumor growth while α-tocopherol had no effect after 30 weeks of feeding diets containing α-, δ-, or γ-tocopherols.…”