Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice.
Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice.
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脑中硒蛋白的表达受损会触发纹状体神经元丧失，从而导致小鼠的协同缺陷。
DOI：
10.1042/bj20140423
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发表时间：
2014-08-15
期刊：
影响因子：
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通讯作者：
Schweizer U
中科院分区：
文献类型：
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作者：
Seeher S;Carlson BA;Miniard AC;Wirth EK;Mahdi Y;Hatfield DL;Driscoll DM;Schweizer U
硒代半胱氨酸插入序列 (SECIS) 结合蛋白 2 (Secisbp2) 与位于真核硒蛋白 mRNA 3' 非翻译区的 SECIS 元件结合。它有助于响应 UGA 密码子而掺入稀有氨基酸硒代半胱氨酸。肝细胞中 Secisbp2 的失活大大降低了硒蛋白水平。 Secisbp2 (CamK-Cre; Secisbp2fl/fl) 的神经元特异性失活比 tRNA[Ser]Sec 失活降低了大脑中硒蛋白表达的程度。这使我们能够研究皮质小白蛋白阳性 (PV+) 中间神经元的发育，这些中间神经元在 tRNA[Ser]Sec 突变体中完全丢失。体感皮层、海马和纹状体中的 PV+ 中间神经元密度降低。 Gad67 的原位杂交证实了 GABA 能中间神经元的减少。由于明显的运动表型涉及广泛的肌张力障碍步态，我们怀疑基底神经节功能障碍。黑质神经元及其纹状体末端的酪氨酸羟化酶表达正常。然而，纹状体 PV+ 和 Gad67+ 神经元的密度分别减少了 65% 和 49%。同样，纹状体胆碱能神经元的密度也减少了 68%。我们的观察表明，几类纹状体中间神经元依赖于硒蛋白的表达。这些发现可能为硒蛋白 P 缺陷小鼠的运动表型以及携带 SECISBP2 突变的患者所描述的运动障碍和精神发育迟滞提供解释。
Selenocysteine Insertion Sequence (SECIS)-Binding Protein 2 (Secisbp2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic selenoprotein mRNAs. It facilitates incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical parvalbumin-positive (PV+) interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus, and striatum. In situ-hybridization for Gad67 confirmed the reduction of GABAergic interneurons. Because of the obvious movement phenotype involving a broad, dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49%, respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.