Fragile X syndrome (FXS) is a leading cause of autism spectrum disorder (ASD) and resulted from a loss of the FMR1-encoded fragile X messenger ribonucleoprotein 1 (FMRP) protein due to large CGG repeat expansions in the promoter region of the FMR1 gene. The microtubule-associated protein Tau is a promising target for Tauopathic diseases and our preliminary study found that Tau protein levels were increased in the brain of Fmr1 knockout (KO) mice, a model of FXS. However, whether Tau reduction can prevent autism-like features in Fmr1 KO mice and become a novel strategy for FXS treatment remain unknown. Tau was genetically reduced in Fmr1 KO mice through crossing Fmr1± female mice with Mapt± male mice. The male offspring with different genotypes were subjected to various autism-related behavioral tests, RNA sequencing, and biochemical analysis. Fmr1 KO male mice were treated with Tau-targeting antisense oligonucleotide (ASO) and then subjected to behavioral tests and biochemical analysis. Tau expression was increased in the cortex of Fmr1 KO mice. Genetically reducing Tau prevented social defects, stereotyped and repetitive behavior, and spine abnormality in Fmr1 KO mice. Tau reduction also reversed increased periodic activity and partially rescued Per1 expression reduction in Fmr1 KO mice. Moreover, Tau reduction reversed compromised P38/MAPK signaling in Fmr1 KO mice. Finally, Tau-targeting ASO also effectively alleviated autism-like phenotypes and promoted P38/MAPK signaling in Fmr1 KO mice. Our study is limited to male mice, in agreement with the higher incidence of FXS in males than females. Whether Tau reduction also exerts protection in females deserves further scrutiny. Moreover, although Tau reduction rescues impaired P38/MAPK signaling in Fmr1 KO mice, whether this is the responsible molecular mechanism requires further determination. Our data indicate that Tau reduction prevents autism-like phenotypes in Fmr1 KO mice. Tau may become a new target for FXS treatment.

中文翻译：

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Tau 蛋白减少可减弱 Fmr1 敲除小鼠的自闭症样特征

脆性 X 综合征 (FXS) 是自闭症谱系障碍 (ASD) 的主要原因，是由于 FMR1 基因启动子区域的大量 CGG 重复扩增导致 FMR1 编码的脆性 X 信使核糖核蛋白 1 (FMRP) 蛋白丢失所致。 。微管相关蛋白 Tau 是 Tau 病疾病的一个有前景的靶标，我们的初步研究发现，Fmr1 敲除 (KO) 小鼠（FXS 模型）的大脑中 Tau 蛋白水平升高。然而，Tau 减少是否可以预防 Fmr1 KO 小鼠的自闭症样特征并成为 FXS 治疗的新策略仍不清楚。通过将 Fmr1± 雌性小鼠与 Mapt± 雄性小鼠杂交，Fmr1 KO 小鼠中的 Tau 基因减少。具有不同基因型的雄性后代接受了各种与自闭症相关的行为测试、RNA测序和生化分析。Fmr1 KO 雄性小鼠用 Tau 靶向反义寡核苷酸 (ASO) 处理，然后进行行为测试和生化分析。Fmr1 KO 小鼠皮质中的 Tau 表达增加。基因减少 Tau 可预防 Fmr1 KO 小鼠的社会缺陷、刻板和重复行为以及脊柱异常。Tau 减少还逆转了 Fmr1 KO 小鼠周期性活动的增加并部分挽救了 Per1 表达的减少。此外，Tau 蛋白的减少逆转了 Fmr1 KO 小鼠中受损的 P38/MAPK 信号传导。最后，Tau 靶向 ASO 还有效缓解了 Fmr1 KO 小鼠的自闭症样表型并促进了 P38/MAPK 信号传导。我们的研究仅限于雄性小鼠，这与雄性小鼠 FXS 的发病率高于雌性小鼠的事实一致。Tau蛋白减少是否也对女性产生保护作用值得进一步研究。此外，虽然 Tau 减少可以挽救 Fmr1 KO 小鼠中受损的 P38/MAPK 信号传导，但这是否是负责的分子机制需要进一步确定。我们的数据表明，Tau 蛋白减少可以预防 Fmr1 KO 小鼠的自闭症样表型。Tau可能成为FXS治疗的新靶点。