GATM and GAMT synthesize creatine locally throughout the mammalian body and within oligodendrocytes of the brain

Abstract

The enzymes glycine amidinotransferase, mitochondrial (GATM also known as AGAT) and guanidinoacetate N-methyltransferase (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.

Keywords: AGAT; Creatine metabolism; GAMT; GATM; Neuron; Oligodendrocyte.