Abstract：
Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of \"non-essential\" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.
摘要：
SLC1A4转运蛋白的突变导致神经发育障碍，痉挛性四肢瘫痪,薄的call体，和儿童的小头畸形。SLC1A4催化中性氨基酸之间的强制性氨基酸交换，但SLC1A4疾病突变和进行性小头畸形的病理生理学仍不清楚.这里,我们检查了三种Slc1a4小鼠模型的表型和代谢谱，包括一只组成型Slc1a4-KO小鼠，具有主要人类Slc1a4突变（Slc1a4-K256E）的敲入小鼠，和在脑内皮细胞中选择性敲除Slc1a4(Slc1a4tie2-cre)。我们表明Slc1a4是BBB上真正的L-丝氨酸转运蛋白，并且Slc1a4的急性抑制或缺失导致丝氨酸流入大脑的减少。这导致与大脑中L-丝氨酸含量降低相关的小头畸形，大脑中非典型和细胞毒性1-脱氧鞘脂的积累，神经变性,突触和线粒体异常，和行为障碍。产前和出生后早期口服L-丝氨酸的水平可以补充大脑中的丝氨酸池，从而挽救了观察到的生化和行为变化。在Slc1a4-E256K小鼠中，直到出生后第二周的L-丝氨酸的施用也使脑重量正常化。我们的观察表明，“非必需”氨基酸从血液中通过血脑屏障的运输至少与必需氨基酸对脑代谢和发育同样重要。我们提出，SLC1A4突变会导致BBB氨基酸病，在BBB中丝氨酸导入不足，这是最佳脑生长所必需的，并导致代谢性小头畸形。其可适于用L-丝氨酸处理。
