Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome.

中文翻译：

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由于脆弱的X智力低下蛋白的丧失，前颗粒蛋白升高会导致突触和学习障碍

脆性X综合征是由于脆性X智力低下蛋白（FMRP，由FMR1基因编码）丧失而引起的智力残疾的可遗传形式。缺乏FMRP会导致原发性肿瘤坏死因子受体配体原粒蛋白（PGRN，由GRN编码）的过度表达。在本研究中，我们发现Fmr1基因敲除小鼠的内侧前额叶皮层中的前颗粒蛋白mRNA和蛋白上调。在Fmr1基因敲除小鼠中，前颗粒蛋白升高会导致Fmr1内侧前额叶皮层的树突状修剪不足和后期长期长期增强剔除小鼠。Fgr1基因敲除小鼠中的部分前颗粒蛋白敲除可恢复脊柱形态并逆转行为缺陷，包括恐惧记忆，活动亢进和运动不灵活性受损。前颗粒蛋白可增加培养的野生型神经元中磷酸化谷氨酸离子受体GluA1和核因子κB的水平。肿瘤坏死因子受体2抗体灌注阻断了前颗粒蛋白对GluA1磷酸化的影响；该结果表明肿瘤坏死因子受体2是前颗粒蛋白介导的GluA1磷酸化和晚期长期增强表达所必需的。但是，Fmr1中的基础颗粒蛋白原水平较高剔除小鼠阻止了外源性颗粒蛋白进一步促进突触可塑性。前颗粒蛋白或肿瘤坏死因子受体2 /核因子κB信号的部分下调恢复了Fmr1基因敲除小鼠的突触可塑性和记忆缺陷。这些发现表明，PGRN升高与脆性X综合征的认知缺陷有关，而前颗粒蛋白/肿瘤坏死因子受体2信号通路可能是改善脆性X综合征认知缺陷的公认治疗靶点。