Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency
Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency
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DOI：
10.1007/s10545-006-0247-6
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发表时间：
2006-02-01
影响因子：
4.2
通讯作者：
Gibson, KM
中科院分区：
文献类型：
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作者：
Donarum, EA;Stephan, DA;Gibson, KM
琥珀酸半醛脱氢酶（SSADH）缺乏症是一种罕见的GABA降解遗传缺陷，最近在小鼠（SSADH（-/-）小鼠）中建模，表现为早期失神癫痫发作，在基因消融小鼠中演变为全身性惊厥发作和致死性癫痫持续状态。破坏GABA稳态，与癫痫表型和增加γ-羟丁酸（GHB），表明表达谱与U 74 Av 2亲和系统将揭示与GABA能和多巴胺能神经传递相关的受体基因的失调。出乎意料的是，我们发现与髓鞘生物发生和压实相关的基因显著下调，主要在海马和皮质。这些结果通过以下方法证实：（1）髓鞘碱性蛋白（MBP）免疫组织化学;（2）髓鞘相关糖蛋白（MAG）和MBP的蛋白质印迹;（3）海马、皮质和脊髓中髓鞘相关少突胶质细胞碱性蛋白（MOBP）、MAG、MBP和蛋白脂质蛋白（PLP）的qRT-PCR分析;（4）乙醇胺和胆碱缩醛磷脂（所有核心髓鞘组分）的定量;（5）使用甲苯胺蓝染色评价脑切片中的髓鞘含量;和（6）通过电子显微镜评价髓鞘厚度的超微结构。我们推测，通过GABA能系统起作用的GABA/GHB增加导致神经类固醇孕酮和别孕烯醇酮的水平降低[Gupta et al（2003）Ann Neurol 54（Supplement 6）：S81-S90]和促分裂原活化蛋白（MAP）激酶的磷酸化，导致主要在SSADH（-/-）小鼠的皮质中的髓鞘蛋白异常。
Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH(-/-) mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol 54(Supplement 6): S81-S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH(-/-) mice.