GATM and GAMT synthesize creatine locally throughout the mammalian body and within oligodendrocytes of the brain
GATM and GAMT synthesize creatine locally throughout the mammalian body and within oligodendrocytes of the brain
复制标题
DOI：
10.1016/j.brainres.2021.147627
复制
发表时间：
2021-08-23
期刊：
影响因子：
2.9
通讯作者：
Montine, Thomas J.
中科院分区：
文献类型：
--
作者：
Baker, Steven Andrew;Gajera, Chandresh R.;Montine, Thomas J.
酶甘氨酸脒基转移酶、线粒体（GATM也称为AGAT）和胍基乙酸N甲基转移酶（GAMT）一起起作用以从精氨酸、甘氨酸和S-腺苷甲硫氨酸合成肌酸。酶或肌酸转运蛋白CT 1的缺乏会导致毁灭性的神经系统疾病，即脑肌酸缺乏综合征（CCDS）。为了更好地了解CCDS的病理生理学，我们利用RNA测序分析结合体内免疫荧光（IF），以单细胞分辨率绘制了GATM和GAMT的分布图。使用小鼠作为模型系统，我们发现，GATM和GAMT的共表达在几个组织中具有不同的和重叠的细胞来源，暗示本地合成肌酸代谢的重要机制，在许多器官。在RNA水平上扩展先前的发现，我们的分析表明，少突胶质细胞表达的Gatm和Gamt的任何细胞类型在体内的最高水平。我们证实了这一发现在小鼠大脑中的IF，其中GATM定位于少突胶质细胞的线粒体，而少突胶质细胞和大脑皮层神经元表达GAMT。有趣的是，后者缺乏GATM。4个脑区域的转座酶可及染色质测序（snATAC-seq）分析的单核测定突出了少突胶质细胞在人类中枢神经系统中GATM和GAMT表达中的相似的首要性。重要的是，在少突胶质细胞中检测到人GATM内含子2内的活性推定调控元件，但在神经元中未检测到。
The enzymes glycine amidinotransferase, mitochondrial (GATM also known as AGAT) and guanidinoacetate Nmethyltransferase (GAMT) function together to synthesize creatine from arginine, glycine, and S-Adenosyl methionine. Deficiency in either enzyme or the creatine transporter, CT1, results in a devastating neurological disorder, Cerebral Creatine Deficiency Syndrome (CCDS). To better understand the pathophysiology of CCDS, we mapped the distribution of GATM and GAMT at single cell resolution, leveraging RNA sequencing analysis combined with in vivo immunofluorescence (IF). Using the mouse as a model system, we find that GATM and GAMT are coexpressed in several tissues with distinct and overlapping cellular sources, implicating local synthesis as an important mechanism of creatine metabolism in numerous organs. Extending previous findings at the RNA level, our analysis demonstrates that oligodendrocytes express the highest level of Gatm and Gamt of any cell type in the body. We confirm this finding in the mouse brain by IF, where GATM localizes to the mitochondria of oligodendrocytes, whereas both oligodendrocytes and cerebral cortical neurons express GAMT. Interestingly, the latter is devoid of GATM. Single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) analysis of 4 brain regions highlights a similar primacy of oligodendrocytes in the expression of GATM and GAMT in the human central nervous system. Importantly, an active putative regulatory element within intron 2 of human GATM is detected in oligodendrocytes but not neurons.