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 language | English (US) |
|---|---|
| Pages (from-to) | 289-302 |
| Number of pages | 14 |
| Journal | Free Radical Biology and Medicine |
| Volume | 120 |
| DOIs | |
| State | Published - May 20 2018 |
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Keywords
- RNA-sequencing
- Transcription
- Vitamin E
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)
Cite this
An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice. / Finno, Carrie J; Bordbari, Matthew H.; Gianino, Giuliana; Ming-Whitfield, Brittni; Burns, Erin; Merkel, Janel; Britton, Monica; Durbin-Johnson, Blythe; Sloma, Erica A.; McMackin, Marissa; Cortopassi, Gino A; Rivas, Victor; Barro, Marietta; Tran, Cecilia K.; Gennity, Ingrid; Habib, Hadi; Xu, Libin; Puschner, Birgit; Miller, Andrew D.
In: Free Radical Biology and Medicine, Vol. 120, 20.05.2018, p. 289-302.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice
AU - Finno, Carrie J
AU - Bordbari, Matthew H.
AU - Gianino, Giuliana
AU - Ming-Whitfield, Brittni
AU - Burns, Erin
AU - Merkel, Janel
AU - Britton, Monica
AU - Durbin-Johnson, Blythe
AU - Sloma, Erica A.
AU - McMackin, Marissa
AU - Cortopassi, Gino A
AU - Rivas, Victor
AU - Barro, Marietta
AU - Tran, Cecilia K.
AU - Gennity, Ingrid
AU - Habib, Hadi
AU - Xu, Libin
AU - Puschner, Birgit
AU - Miller, Andrew D.
PY - 2018/5/20
Y1 - 2018/5/20
N2 - 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.
AB - 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.
KW - RNA-sequencing
KW - Transcription
KW - Vitamin E
UR - http://www.scopus.com/inward/record.url?scp=85044978221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044978221&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2018.02.037
DO - 10.1016/j.freeradbiomed.2018.02.037
M3 - Article
C2 - 29526809
AN - SCOPUS:85044978221
VL - 120
SP - 289
EP - 302
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
ER -