Amelioration of Behavioral Abnormalities in BH4-deficient Mice by Dietary Supplementation of Tyrosine

This study reports an amelioration of abnormal motor behaviors in tetrahydrobiopterin (BH4)-deficient Spr−/− mice by the dietary supplementation of tyrosine. Since BH4 is an essential cofactor for the conversion of phenylalanine into tyrosine as well as the synthesis of dopamine neurotransmitter within the central nervous system, the levels of tyrosine and dopamine were severely reduced in brains of BH4-deficient Spr−/− mice. We found that Spr−/− mice display variable ‘open-field’ behaviors, impaired motor functions on the ‘rotating rod’, and dystonic ‘hind-limb clasping’. In this study, we report that these aberrant motor deficits displayed by Spr−/− mice were ameliorated by the therapeutic tyrosine diet for 10 days. This study also suggests that dopamine deficiency in brains of Spr−/− mice may not be the biological feature of aberrant motor behaviors associated with BH4 deficiency. Brain levels of dopamine (DA) and its metabolites in Spr−/− mice were not substantially increased by the dietary tyrosine therapy. However, we found that mTORC1 activity severely suppressed in brains of Spr−/− mice fed a normal diet was restored 10 days after feeding the mice the tyrosine diet. The present study proposes that brain mTORC1 signaling pathway is one of the potential targets in understanding abnormal motor behaviors associated with BH4-deficiency.

本研究报道，通过膳食补充酪氨酸可改善四氢生物蝶呤（tetrahydrobiopterin, BH4）缺陷型Spr−/−小鼠的异常运动行为。鉴于BH4是苯丙氨酸转化为酪氨酸以及中枢神经系统内多巴胺神经递质合成的必需辅因子，BH4缺陷型Spr−/−小鼠脑内酪氨酸与多巴胺的水平会显著降低。我们发现，Spr−/−小鼠表现出多样化的旷场实验（open-field）行为异常、旋转杆实验（rotating rod）中的运动功能受损，以及肌张力障碍性后肢抱持（hind-limb clasping）现象。本研究证实，为期10天的治疗性酪氨酸膳食干预，可缓解Spr−/−小鼠出现的上述运动功能缺陷。本研究同时提示，Spr−/−小鼠脑内的多巴胺缺乏，或许并非BH4缺陷相关异常运动行为的核心生物学特征。膳食酪氨酸治疗并未显著提升Spr−/−小鼠脑内多巴胺（dopamine, DA）及其代谢产物的水平。但我们观察到，正常膳食喂养的Spr−/−小鼠脑内mTORC1（哺乳动物雷帕霉素靶蛋白复合物1）活性严重受抑，而在接受酪氨酸膳食喂养10天后，该活性得以恢复。本研究提出，脑内mTORC1信号通路是解析BH4缺陷相关异常运动行为的潜在靶点之一。