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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice
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Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

机译：抑制p21激活的激酶可挽救小鼠脆性X综合征的症状

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Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereo-typy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.
机译：脆性X综合征（FXS）是弱智和自闭症最常见的遗传形式，是由脆性X智力低下1（FMR1）基因的转录沉默和脆性X智力低下蛋白的丧失引起的。尽管越来越多的证据表明特定受体和生化途径在FXS发病机理中的作用，但尚未开发出有效的治疗方法。在这里，我们报告说，通过抑制p21活化激酶（PAK）的催化活性，至少在细胞和行为水平上都至少部分改善了FMR1基因敲除（KO）小鼠（FXS的动物模型）中的异常，已知在肌动蛋白聚合和树突棘形态发生中起关键作用的激酶。 FXS中常见的形态学突触异常，皮质中更大的脊柱密度和细长的棘突，至少在出生后通过前脑中的显性负（dn）PAK转基因表达得以部分恢复。同样，通过dnPAK转基因可以完全恢复FMR1 KO小鼠中皮质长期增强的缺陷。 dnPAK转基因还可以部分或完全缓解与FMR1 KO小鼠相关的几种行为异常，包括运动能力异常，刻板印象，焦虑和痕量恐惧条件的异常。最后，我们证明了PAK与脆性X智力低下蛋白在体外之间的直接相互作用。总体而言，我们的结果证明了FXS小鼠模型的表型遗传拯救，并表明PAK信号通路（包括PAK的催化活性）是FXS和自闭症治疗发展的新型干预部位。

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