Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency.

l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT) mice and AGAT mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (, ), creatine metabolism (), cerebral myelination () and neuronal excitability (). While and showed regulation by hArg supplementation, and were creatine dependent. Additional regulated genes such as and need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of and . Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.