Creatine deficiency syndromes and the importance of creatine synthesis in the brain
Creatine deficiency syndromes and the importance of creatine synthesis in the brain
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DOI：
10.1007/s00726-011-0852-z
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发表时间：
2011-05-01
期刊：
影响因子：
3.5
通讯作者：
Uldry, Josephine
中科院分区：
文献类型：
--
作者：
Braissant, Olivier;Henry, Hugues;Uldry, Josephine
由于AGAT、GAMT（肌酸合成途径）或SLC6A8（肌酸转运蛋白）的缺乏，肌酸缺乏综合征导致CNS中肌酸完全缺失或非常强烈的减少，如通过磁共振波谱法测量的。脑是肌酐缺乏患者的主要受累器官，这些患者在婴儿早期表现出严重的神经发育迟缓和神经系统症状。AGAT和GAMT缺乏的患者可以通过口服肌酸补充剂来治疗，这可以改善他们的神经系统状态，而这种治疗对SLC6A8缺乏的患者无效。虽然长期以来一直认为大部分（如果不是全部）脑肌酸是外周来源的，但过去几年的证据表明，肌酸可以穿过血脑屏障，但是效率很低，并且CNS必须通过其自身的内源性合成来确保其肌酸需求的一部分。此外，我们最近发现，在许多大脑结构中，包括皮层和基底神经节，AGAT和GAMT，虽然在每种脑细胞类型中发现，但并不共表达，而是以分离的方式表达。这表明，为了使肌酸在这些结构中合成，胍基乙酸必须从AGAT表达细胞转运到GAMT表达细胞，最有可能是通过SLC6A8。肌酸代谢和运输在中枢神经系统中的新的理解不仅可以更好地理解肌酸缺乏综合征的大脑后果，但也将有助于更好地破译肌酸在中枢神经系统中的作用，不仅在能量作为ATP再生和缓冲，而且在其最近提出的功能作为神经递质或渗透。
Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT- and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.