Abnormal Amino Acid Profiles of Blood and Cerebrospinal Fluid from Cystathionine β-Synthase-Deficient Mice, an Animal Model of Homocystinuria
Abnormal Amino Acid Profiles of Blood and Cerebrospinal Fluid from Cystathionine β-Synthase-Deficient Mice, an Animal Model of Homocystinuria
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DOI：
10.1248/bpb.b19-00127
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发表时间：
2019-06-01
影响因子：
2
通讯作者：
Ishii, Isao
中科院分区：
文献类型：
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作者：
Akahoshi, Noriyuki;Yokoyama, Akira;Ishii, Isao
智力低下是先天性氨基酸代谢缺陷中最常见的特征。由于胱硫醚β-合酶（CBS）缺乏引起的同型胱氨酸尿症/同型半胱氨酸血症患者，从小就患有血栓栓塞和智力低下;因此，通过新生儿筛查进行检测。此外，妊娠期间血清同型半胱氨酸水平升高与新生儿神经管缺陷（NTDs）的发生有关。然而，这种中枢神经系统（CNS）缺陷的原因是未知的。我们发现以前受损的学习能力在Cbs缺陷（Cbs（-/-））小鼠（但不是NTD出生）。在这里，我们调查了从Cbs（-/-）小鼠的血清和脑脊液（CSF）的氨基酸谱。作为对照，分析了缺乏胱硫醚γ-裂解酶（Cth）（转硫作用中CBS的下游酶）的小鼠以及野生型小鼠。Cbs（-/-）和Cth（-/-）小鼠比野生型小鼠小，并且Cbs（-/-）小鼠的CSF产量比其他小鼠低。CSF氨基酸水平通常低于血清中的氨基酸水平，并且与Cb（-/-）小鼠血清中氨基酸水平的显著变化相比，CSF中的变化不太明显。然而，在Cbs（-/-）小鼠CSF中发现天冬氨酸/天冬酰胺（Asp/Asn）、谷氨酰胺（Gln）、丝氨酸（Ser）、苏氨酸（Thr）、苯丙氨酸（Phe）、酪氨酸（Tyr）、甲硫氨酸（Met）、总同型半胱氨酸和瓜氨酸显著上调（与野生型相比），赖氨酸（Lys）下调。由于在Cth（-/-）小鼠的CSF中观察到总同型半胱氨酸/瓜氨酸/赖氨酸的类似调节，这些小鼠没有CNS功能障碍，因此CSF体积减少和其他氨基酸水平变化可能与Cbs（-/-）特异性CNS缺陷相关。
Mental retardation is the most common feature among inborn errors of amino acid metabolism. Patients with homocystinuria/homocysteinemia caused by cystathionine beta-synthase (CBS) deficiency suffer from thromboembolism and mental retardation from early ages; therefore, detection by newborn screening is performed. Furthermore, elevated levels of serum homocysteine during pregnancy are associated with the occurrence of neural tube defects (NTDs) in newborns. However, the causes of such central nervous system (CNS) defects are unknown. We found previously impaired learning abilities in Cbs-deficient (Cbs(-/-)) mice (but not NTD births). Here, we investigated the amino acid profiles of serum and cerebrospinal fluid (CSF) from Cbs(-/-) mice. Mice deficient in cystathionine gamma-lyase (Cth), a downstream enzyme of CBS in transsulfuration, as well as wild-type mice, were analyzed as controls. Cbs(-/-) and Cth(-/-) mice were smaller than wild type mice, and CSF yields in Cbs(-/-) mice were lower than the others. CSF amino acid levels were generally lower than those in serum, and compared with the dramatic amino acid level alterations in Cbs(-/-) mouse serum, alterations in CSF were less apparent. However, marked upregulation (versus wild-type) of aspartic acid/asparagine (Asp/Asn), glutamine (Gin), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), methionine (Met), total homocysteine, and citrulline, and downregulation of lysine (Lys) were found in Cbs(-/-) mouse CSF. Because similar regulation of total homocysteine/citrulline/Lys was observed in the CSF of Cth(-/-) mice, which are free of CNS dysfunction, the reduced CSF volumes and the level changes of other amino acids could be relevant to Cbs(-/-)-specific CNS defects.