α-tocopherol transfer protein deficiency in mice causes multi-organ deregulation of gene networks and behavioral deficits with age
α-tocopherol transfer protein deficiency in mice causes multi-organ deregulation of gene networks and behavioral deficits with age
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DOI：
10.1196/annals.1331.012
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Traber, MG
中科院分区：
文献类型：
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作者：
Gohil, K;Godzdanker, R;Traber, MG
α -生育酚（α -t）在体内的功能，除了那些在女性生育，是激烈的争论。在共济失调（AVED）患者中发现α -t缺乏症，随后在AVED患者中发现编码α -生育酚转移蛋白（TTP）的基因突变，这表明α -t和TTP对正常神经功能至关重要。导致α - t敏感神经功能障碍的α - t分子靶点仍有待发现。我们使用高密度寡核苷酸阵列，在小鼠出生时由于TTP基因缺失而导致的α - t缺乏的体内模型中，在中枢神经系统和其他组织中寻找可能的α - t敏感基因。在α - t缺陷小鼠的运动皮层中发现了影响突触功能和髓鞘形成的基因的抑制和神经变性基因的诱导。在ttp缺陷小鼠的皮质和肾上腺中，维甲酸相关孤儿受体α (ror - α)的表达受到抑制。在小鼠中，ror - α的缺乏导致共济失调，这可能是导致冠心病患者共济失调的原因。这些观察结果表明，α - t的一些作用是由转录因子ror - α介导的。年轻的ttp缺失小鼠的行为基本正常，但老年小鼠表现出不活动、共济失调和记忆功能障碍。老年α - t缺陷大脑皮层mRNA谱与少突胶质细胞活性抑制相一致；和星形胶质细胞。总之，基因表达谱研究已经确定了中枢神经系统中新的α - t调节基因和细胞，它们可能与延迟性神经退行性变和与年龄相关的行为能力下降有关。
Functions of alpha-tocopherol (alpha-T) in vivo, other than those for fertility in females, are intensely debated. The discovery of alpha-T deficiency in patients with ataxia (AVED) followed by the identification of mutations in the gene encoding alpha-tocopherol transfer protein (TTP) in AVED patients demonstrates an essential role of alpha-T and TTP for normal neurological function. alpha-T molecular targets that account for alpha-T-sensitive neurological dysfunction remain to be discovered. We have used high-density oligonucleotide arrays to search for putative alpha-T-sensitive genes in the CNS and other tissues in an in vivo model of alpha-T deficiency imposed at birth by the deletion of the TTP gene in mice. Repression of genes affecting synaptic function and myelination and induction of genes for neurodegeneration in the motor cortex of alpha-T-deficient mice were identified. The expression of retinoic acid-related orphan receptor alpha (ROR-alpha) was repressed in the cortex and adrenal glands of TTP-deficient mice. Deficiency of ROR-alpha causes ataxia in mice and may account for ataxia in AVED patients. These observations suggest that some of the actions of alpha-T are mediated by the transcription factor ROR-alpha. The behavior of young TTP-null mice was essentially normal, but older mice showed inactivity, ataxia, and memory dysfunction. mRNA profiles of old alpha-T-deficient cerebral cortices are compatible with repressed activity of oligodendrocytes; and astrocytes. In conclusion, gene-expression profiling studies have identified novel alpha-T-modulated genes and cells in the CNS that may be causatively linked with delayed neurodegeneration and age-related decline in behavioral repertoires.