Abstract：
Phenylketonuria is characterized by the accumulation of phenylalanine, resulting in severe cognitive and neurological disorders if not treated by a remarkably strict diet. There are two approved drugs today, yet both provide only a partial solution. We have previously demonstrated the formation of amyloid-like toxic assemblies by aggregation of phenylalanine, suggesting a new therapeutic target to be further pursued. Moreover, we showed that compounds that halt the formation of these assemblies also prevent their resulting toxicity. Here, we performed high-throughput screening, searching for compounds with inhibitory effects on phenylalanine aggregation. Morin hydrate, one of the most promising hits revealed during the screen, was chosen to be tested in vivo using a phenylketonuria mouse model. Morin hydrate significantly improved cognitive and motor function with a reduction in the number of phenylalanine brain deposits. Moreover, while phenylalanine levels remained high, we observed a recovery in dopaminergic, adrenergic, and neuronal markers. To conclude, the ability of Morin hydrate to halt phenylalanine aggregation without reducing phenylalanine levels implies the toxic role of the phenylalanine assemblies in phenylketonuria and opens new avenues for disease-modifying treatment.
摘要：
苯丙酮尿症的特征是苯丙氨酸的积累，如果不通过非常严格的饮食治疗，会导致严重的认知和神经系统疾病。今天有两种批准的药物，然而，两者都只提供了部分解决方案。我们以前已经证明了通过聚集苯丙氨酸形成淀粉样蛋白样毒性组件，建议进一步追求新的治疗目标。此外，我们表明，化合物，停止形成这些组件也防止其产生的毒性。这里,我们进行了高通量筛选，寻找对苯丙氨酸聚集有抑制作用的化合物。Morin水合物,屏幕上最有希望的热门歌曲之一，选择使用苯丙酮尿症小鼠模型进行体内测试。Morin水合物显着改善了认知和运动功能，减少了苯丙氨酸脑沉积物的数量。此外，而苯丙氨酸水平仍然很高，我们观察到多巴胺能恢复，肾上腺素能,和神经元标记。最后，Morin水合物能够在不降低苯丙氨酸水平的情况下阻止苯丙氨酸聚集,这意味着苯丙酮尿症中苯丙氨酸集合的毒性作用,并为疾病改善治疗开辟了新的途径.
