Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease.
Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease.
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DOI：
10.1186/1750-1172-9-73
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发表时间：
2014-05-08
影响因子：
3.7
通讯作者：
Gibson KM
中科院分区：
文献类型：
--
作者：
Vogel KR;Arning E;Wasek BL;McPherson S;Bottiglieri T;Gibson KM
枫糖浆尿病(MSUD)患者的常规治疗需要限制蛋白质摄入，以保持血液中监测的支链氨基酸亮氨酸(LEU)的可接受水平。然而，目前还没有关于大脑和血液中的LEU与蛋白质限制的相关性，以及血液中的校正是否反映在大脑中的数据。为了解决这个问题，我们用19%(标准)和6%蛋白质的中间饲料喂养MSUD小鼠，收集血清(SE)、纹状体(STR)、小脑(CE)和皮质(CTX)进行氨基酸定量分析。当蛋白质含量从19%提高到6%时，所有大脑区域的亮氨酸和缬氨酸(Val)水平平均提高了28%，而SE的相同水平平均提高了60%。大脑区域的异亮氨酸(Ile)水平没有改善，而SE水平在低蛋白质消耗的情况下提高了24%。血液支链氨基酸(血清中的亮氨酸、异亮氨酸和缬氨酸)为362-434μM，与控制范围内的人的值一致。然而，尽管蛋白质限制，脑区的许多氨基酸仍然异常，包括谷氨酰胺(Gln)、天冬氨酸(ASP)、谷氨酸(GLU)、γ-氨基丁酸(GABA)、天冬氨酸(ASN)、瓜氨酸(CIT)和丝氨酸(SER)。为了评估这些异常的特异性，我们在高苯丙氨酸血症小鼠中进行了初步研究，模拟了另一种大型中性氨基酸病。采用相同的饮食方案，我们发现GLN、ASP和GLU的异常非常一致。我们的结果表明，血液氨基酸分析可能是评估蛋白质限制在大型中性氨基酸病中的转归的一个很差的替代指标，并进一步表明慢性神经递质中断(GLU、GABA、ASP)可能导致这些疾病的长期神经认知功能障碍。
Conventional therapy for patients with maple syrup urine disease (MSUD) entails restriction of protein intake to maintain acceptable levels of the branched chain amino acid, leucine (LEU), monitored in blood. However, no data exists on the correlation between brain and blood LEU with protein restriction, and whether correction in blood is reflected in brain. To address this question, we fed intermediate MSUD mice diets of 19% (standard) and 6% protein, with collection of sera (SE), striata (STR), cerebellum (CE) and cortex (CTX) for quantitative amino acid analyses. LEU and valine (VAL) levels in all brain regions improved on average 28% when shifting from 19% to 6% protein, whereas the same improvements in SE were on average 60%. Isoleucine (ILE) in brain regions did not improve, while the SE level improved 24% with low-protein consumption. Blood-branched chain amino acids (LEU, ILE, and VAL in sera (SE)) were 362-434 μM, consistent with human values considered within control. Nonetheless, numerous amino acids in brain regions remained abnormal despite protein restriction, including glutamine (GLN), aspartate (ASP), glutamate (GLU), gamma-aminobutyric acid (GABA), asparagine (ASN), citrulline (CIT) and serine (SER). To assess the specificity of these anomalies, we piloted preliminary studies in hyperphenylalaninemic mice, modeling another large neutral aminoacidopathy. Employing an identical dietary regimen, we found remarkably consistent abnormalities in GLN, ASP, and GLU. Our results suggest that blood amino acid analysis may be a poor surrogate for assessing the outcomes of protein restriction in the large neutral amino acidopathies, and further indicate that chronic neurotransmitter disruptions (GLU, GABA, ASP) may contribute to long-term neurocognitive dysfunction in these disorders.
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影响因子：
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作者：
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通讯作者：
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13.5
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通讯作者：
Strom, Stephen C.