Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder characterized by variable expressivity. TSC results from inactivating variants within the TSC1 or TSC2 genes, leading to constitutive activation of mechanistic target of rapamycin complex 1 signaling. Using a mouse model of TSC (Tsc2-RG) in which the Tsc2 gene is deleted in radial glial precursors and their neuronal and glial descendants, we observed increased ornithine decarboxylase (ODC) enzymatic activity and concentration of its product, putrescine. To test if increased ODC activity and dysregulated polyamine metabolism contribute to the neurodevelopmental defects of Tsc2-RG mice, we used pharmacologic and genetic approaches to reduce ODC activity in Tsc2-RG mice, followed by histologic assessment of brain development. We observed that decreasing ODC activity and putrescine levels in Tsc2-RG mice worsened many of the neurodevelopmental phenotypes, including brain growth and neuronal migration defects, astrogliosis and oxidative stress. These data suggest a protective effect of increased ODC activity and elevated putrescine that modify the phenotype in this developmental Tsc2-RG model.

中文翻译：

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鸟氨酸脱羧酶是多胺合成的限速酶，可改变结节性硬化症小鼠模型的脑病理学。


结节性硬化症（TSC）是一种罕见的常染色体显性神经发育障碍，其特征是表达性可变。 TSC 是由TSC1或TSC2基因内的失活变异引起的，导致雷帕霉素复合物 1 信号传导机制靶标的组成型激活。使用 TSC ( Tsc2-RG ) 小鼠模型，其中放射状胶质前体及其神经元和胶质后代中的Tsc2基因被删除，我们观察到鸟氨酸脱羧酶 (ODC) 酶活性及其产物腐胺浓度增加。为了测试ODC活性增加和多胺代谢失调是否会导致Tsc2-RG小鼠的神经发育缺陷，我们使用药理学和遗传学方法来降低Tsc2-RG小鼠的ODC活性，然后对大脑发育进行组织学评估。我们观察到， Tsc2-RG小鼠中 ODC 活性和腐胺水平的降低使许多神经发育表型恶化，包括大脑生长和神经元迁移缺陷、星形胶质细胞增生和氧化应激。这些数据表明，ODC 活性增加和腐胺升高具有保护作用，可改变发育Tsc2-RG模型中的表型。