Abnormal Amino Acid Profiles of Blood and Cerebrospinal Fluid from Cystathionine β-Synthase-Deficient Mice, an Animal Model of Homocystinuria

Abstract

Mental retardation is the most common feature among inborn errors of amino acid metabolism. Patients with homocystinuria/homocysteinemia caused by cystathionine β-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 γ-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 wildtype 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 (Gln), 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.

Preeclampsia-Like Features and Partial Lactation Failure in Mice Lacking Cystathionine γ-Lyase—An Animal Model of Cystathioninuria

“…Instead, elevated levels of homocyst(e)ine could somehow interfere with oxytocin signaling within the cells (e.g., mammary gland myoepithelial cells). Interestingly, we recently found that the total homocysteine levels of the cerebrospinal fluid were much lower than those of the serum in 2-week-old lactating Cth −/− mice (7.43 versus 184 µM) although both levels were much higher than those in their respective WT mice (1.08 and 13.0 µM, respectively) [57]. This could be the reason for the “semi-” normal oxytocin signaling in the CNS (that regulates maternal behavior in dams and social memory/recognition in males) and the substantially impaired oxytocin signaling in the periphery (that regulates milk ejection/uterine contraction, especially the former in this study).…”

“…This could be the reason for the “semi-” normal oxytocin signaling in the CNS (that regulates maternal behavior in dams and social memory/recognition in males) and the substantially impaired oxytocin signaling in the periphery (that regulates milk ejection/uterine contraction, especially the former in this study). Namely, high circulatory tHcy levels in Cth −/− dams influenced on (high) tHcy in their whey (Table 1) but not circulatory tHcy in their pups (Table 2), and may not affect tHcy in their CNS significantly [57]. Whether hypertension/mild proteinuria in Cth −/− pregnant mice could impair the peripheral oxytocin signaling or vice versa remains unknown.…”

Hyperhomocysteinemia: Metabolic Role and Animal Studies with a Focus on Cognitive Performance and Decline—A Review

“…Although mutations in the Cth gene might even be more prevalent than in the Cbs gene in humans [100], CTH-based models are scarcely utilized in animal research so far, although Cth−/− proved to highly elevate serum and CSF HCys levels [101]. Another example is the betaine homocysteine methyl transferase (BHMT), of which homozygous (Bhmt−/−) and heterozygous (Bhmt+/−) forms were used in order to induce mild HHCys [102].…”

Homocysteine metabolism in rodent models with hyperhomocysteinemia. Part 1: genetic models

“…Особенностью этих моделей является то, что они не только оказывают непосредственное влияние на транссульфурирование, но сильно влияют на метаболизм физиологического вазодилататора H 2 S. Нокаут гена CBS у мышей линии C57B1/6 был одной из первых моделей гомоцистинурии. Она сопровождалась у гомозигот тяжелой ГГц (>200 мкМ) [22]. В спинномозговой жидкости также наблюдался 25-кратный рост уровня Гцис.…”

“…Нокаут гена CSE у мышей C57BL/6 также приводил к тяжелой ГГц (~180 мкМ в плазме крови) и 7-кратному возрастанию его уровня в спинномозговой жидкости [22], при этом существенных изменений уровня Цис и Глн в этих жидкостях при этом не наблюдалось.…”