University Children's Hospital, Division of Child Neurology and Metabolic Diseases, Heidelberg, Germany.
Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Mannheim, Germany.
PLoS One. 2019 Apr 17;14(4):e0215162. doi: 10.1371/journal.pone.0215162. eCollection 2019.
Dihydropteridine reductase (QDPR) catalyzes the recycling of tetrahydrobiopterin (BH4), a cofactor in dopamine, serotonin, and phenylalanine metabolism. QDPR-deficient patients develop neurological symptoms including hypokinesia, truncal hypotonia, intellectual disability and seizures. The underlying pathomechanisms are poorly understood. We established a zebrafish model for QDPR deficiency and analyzed the expression as well as function of all zebrafish QDPR homologues during embryonic development. The homologues qdpra is essential for pigmentation and phenylalanine metabolism. Qdprb1 is expressed in the proliferative zones of the optic tectum and eye. Knockdown of qdprb1 leads to up-regulation of pro-proliferative genes and increased number of phospho-histone3 positive mitotic cells. Expression of neuronal and astroglial marker genes is concomitantly decreased. Qdprb1 hypomorphic embryos develop microcephaly and reduced eye size indicating a role for qdprb1 in the transition from cell proliferation to differentiation. Glutamine accumulation biochemically accompanies the developmental changes. Our findings provide novel insights into the neuropathogenesis of QDPR deficiency.
二氢喋呤还原酶（QDPR）催化四氢生物蝶呤（BH4）的循环，BH4 是多巴胺、血清素和苯丙氨酸代谢中的一种辅助因子。QDPR 缺乏的患者会出现运动功能减退、躯干性低张力、智力障碍和癫痫等神经症状。其潜在的发病机制尚不清楚。我们建立了 QDPR 缺乏的斑马鱼模型，并在胚胎发育过程中分析了所有斑马鱼 QDPR 同源物的表达和功能。同源物 qdpra 对于色素沉着和苯丙氨酸代谢是必需的。Qdprb1 在视顶盖和眼睛的增殖区表达。qdprb1 的敲低导致促增殖基因的上调和磷酸化组蛋白 3 阳性有丝分裂细胞数量的增加。神经元和神经胶质标记基因的表达同时减少。qdprb1 功能不全的胚胎表现为小头畸形和眼睛变小，表明 qdprb1 在细胞增殖向分化的转变中起作用。生化上谷氨酰胺的积累伴随着发育变化。我们的研究结果为 QDPR 缺乏的神经发病机制提供了新的见解。
