An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice.
An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice.
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DOI：
10.1016/j.freeradbiomed.2018.02.037
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发表时间：
2018-05-20
影响因子：
7.4
通讯作者：
Miller AD
中科院分区：
文献类型：
--
作者：
Finno CJ;Bordbari MH;Gianino G;Ming-Whitfield B;Burns E;Merkel J;Britton M;Durbin-Johnson B;Sloma EA;McMackin M;Cortopassi G;Rivas V;Barro M;Tran CK;Gennity I;Habib H;Xu L;Puschner B;Miller AD
生育酚（α）转移蛋白基因缺陷的小鼠发生外周生育酚缺陷和感觉神经变性。Ttpa−/−小鼠在6个月龄时出现本体感受缺陷，脊髓背柱内轴突变性和神经元染色质溶解，并向髓质投射。透射电镜下可见背柱轴突变性。我们通过脊髓和小脑内的全局转录组测序来探讨α-TOH缺陷性神经变性的潜在病理机制。Ttpa−/−小鼠脊髓的RNA测序显示，与先天免疫反应相关的基因上调，表明生育酚缺乏导致小胶质细胞活化的分子特征。首次在小鼠脊髓中鉴定出低水平Ttpa表达。此外，转录因子肝X受体（LXR）被α-TOH缺乏强烈激活，触发胆固醇生物合成的失调。转录因子LXR的异常激活抑制了神经稳态所需的转录因子视黄酸相关孤儿受体-α（RORA）的正常诱导。因此，我们发现α-TOH缺乏诱导LXR，这可能导致小胶质细胞活化的分子特征并有助于感觉神经变性。
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.
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影响因子：
2.5
作者：
LANDIS, DMD;SIDMAN, RL
通讯作者：
SIDMAN, RL
DOI：
10.3791/51212
发表时间：
2013-12-19
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Martinov T;Mack M;Sykes A;Chatterjea D
通讯作者：
Chatterjea D
影响因子：
2.7
作者：
Cummings, Brian J.;Engesser-Cesar, Christie;Anderson, Aileen J.
通讯作者：
Anderson, Aileen J.
影响因子：
16.2
作者：
Gold, DA;Baek, SH;Hamilton, BA
通讯作者：
Hamilton, BA
DOI：
10.1196/annals.1331.012
发表时间：
2004-01-01
期刊：
VITAMIN E AND HEALTH
影响因子：
--
作者：
Gohil, K;Godzdanker, R;Traber, MG
通讯作者：
Traber, MG