AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review
AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review
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DOI：
10.1007/s10545-008-0826-9
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发表时间：
2008-04-01
影响因子：
4.2
通讯作者：
Henry, H.
中科院分区：
文献类型：
--
作者：
Braissant, O.;Henry, H.
肌酸缺乏综合征，无论是由于AGAT，GAMT或SLC6A8缺陷，导致完全缺乏，或非常强烈的减少，肌酸在大脑内，如通过磁共振光谱测量。虽然哺乳动物中枢神经系统（CNS）表达AGAT、GAMT和SLC 6A 8，但血脑屏障周围的星形胶质细胞中SLC 6A 8的缺乏限制了大脑从外周输入肌酸的能力，并表明中枢神经系统必须主要依靠通过AGAT和GAMT表达的内源性肌酸合成。这似乎与SLC6A8缺陷相矛盾，尽管AGAT和GAMT表达，SLC6A8缺陷也导致CNS中的肌酸缺乏。我们目前的新数据显示，在皮质灰质，AGAT和GAMT的表达在一个解离的方式：例如，只有少数细胞共表达这两个基因。这表明，为了允许在CNS内合成肌酸，至少对于其中的显著部分，胍基乙酸必须从AGAT表达细胞转运到GAMT表达细胞，可能通过SLC6A8。这将解释在SLC6A8缺陷患者中观察到的肌酸缺乏。通过汇集肌酸缺乏综合征，AGAT，GAMT和SLC6A8在中枢神经系统中的分布，以及肌酸和胍乙酸水平在大脑中的合成视图，这篇综述提出了一个全面的框架，包括新的假设，在正常条件下和肌酸缺乏的情况下，脑肌酸代谢和运输。
Creatine deficiency syndromes, either due to AGAT, GAMT or SLC6A8 deficiencies, lead to a complete absence, or a very strong decrease, of creatine within the brain, as measured by magnetic resonance spectroscopy. While the mammalian central nervous system (CNS) expresses AGAT, GAMT and SLC6A8, the lack of SLC6A8 in astrocytes around the blood-brain barrier limits the brain capacity to import creatine from the periphery, and suggests that the CNS has to rely mainly on endogenous creatine synthesis through AGAT and GAMT expression. This seems contradictory with SLC6A8 deficiency, which, despite AGAT and GAMT expression, also leads to creatine deficiency in the CNS. We present novel data showing that in cortical grey matter, AGAT and GAMT are expressed in a dissociated way: e.g. only a few cells co-express both genes. This suggests that to allow synthesis of creatine within the CNS, at least for a significant part of it, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, possibly through SLC6A8. This would explain the creatine deficiency observed in SLC6A8-deficient patients. By bringing together creatine deficiency syndromes, AGAT, GAMT and SLC6A8 distribution in CNS, as well as a synthetic view on creatine and guanidinoacetate levels in the brain, this review presents a comprehensive framework, including new hypotheses, on brain creatine metabolism and transport, both in normal conditions and in case of creatine deficiency.