Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, Korea.
J Neurochem. 2012 Oct;123(2):226-38. doi: 10.1111/j.1471-4159.2012.07886.x. Epub 2012 Aug 22.
J. Neurochem. (2012) 123, 226-238.
Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when FMR1 gene is mutated. FMR1 encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate in vitro and with middle cerebral artery occlusion (MCAO) in striatal neurons in vivo. Both conditions elicited a rapid, but transient FMRP expression in neurons. This up-regulated FMRP expression was abolished by pre-treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression in vitro or in vivo using small hairpin Fmr1 virus exacerbated cell death by glutamate or MCAO, presumably via hypophosphorylation of Akt and reduced expression of B-cell lymphoma-extra large (Bcl-xL). However, over-expression of FMRP using enhanced green fluorescent protein (eGFP)-FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl-xL production. The pro-survival role of Akt-dependent up-regulation of FMRP in glutamate-stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury.
J.神经化学。（2012 年）123,226-238。
脆性 X 综合征（FXS）是智力迟钝和自闭症谱系疾病的最常见单一遗传原因，发生在 FMR1 基因突变时。FMR1 编码脆性 X 智力迟钝蛋白（FMRP），它调节 mRNA 的翻译，在神经元的发育以及突触的形成和维持中发挥重要作用。为了研究 FMRP 是否调节细胞活力，我们在体外用谷氨酸诱导大鼠原代皮质神经元凋亡，在体内用大脑中动脉闭塞（MCAO）诱导纹状体神经元凋亡。这两种情况都在神经元中迅速但短暂地诱导了 FMRP 的表达。这种上调的 FMRP 表达被 PI3K 和蛋白激酶 B（Akt）抑制剂：LY294002、Akt 抑制剂 IV 和 VIII 的预处理所消除。体外或体内使用短发夹 Fmr1 病毒减少 FMRP 的表达，通过 Akt 的低磷酸化和 B 细胞淋巴瘤-extra large（Bcl-xL）的表达减少，加剧了谷氨酸或 MCAO 引起的细胞死亡。然而，使用增强型绿色荧光蛋白（eGFP）-FMRP 构建体过表达 FMRP 减轻了细胞死亡，增加了 Akt 活性，并增强了 Bcl-xL 的产生。Akt 依赖性上调 FMRP 在谷氨酸刺激的培养神经元以及缺血性脑中的促生存作用在 FXS 以及神经退行性疾病和创伤性脑损伤中可能具有临床重要意义。
