Structure and expression of the glycine cleavage system in rat central nervous system

The glycine cleavage system (GCS) is a mitochondrial multienzyme system con sisting of four individual proteins, three specific components (P-, T-, and H-proteins) and one house-keeping enzyme, dihydrolipoamide dehydrogenase. Inherited deficiency of the GCS causes nonketotic hyperglycinemia (NKH), an inborn error of glycine metabolism. NK-H is characterized by massive accum ulation of glycine in serum and cerebrospinal fluids and severe neuronal dy sfunction in neonates. To elucidate the neuropathogenesis of NKH, we cloned cDNAs encoding three specific components of the GCS and studied the gene e xpression in rat central nervous system. P-, T-, and H-protein cDNAs encode d 1024, 403, and 170 amino acids, respectively. In situ hybridization analy sis revealed that P-protein mRNA was expressed mainly in glial-like cells, including Bergmann glias in the cerebellum, while T- and H-protein mRNAs we re detected in both glial-like cells and neurons. T- and H-protein mRNAs, b ut not P-protein mRNA, were expressed in the spinal cord. Primary astrocyte cultures established from cerebral cortex had higher GCS activities than h epatocytes whereas those from spinal cord expressed only H-protein mRNA and had no enzymatic activity. An important role of glycine as inhibitory neur otransmitter has been established in the brainstem and spinal cord and anot her role of glycine as an excitation modulator of N-methyl-D-aspartate rece ptor is suggested in the hippocampus, cerebral cortex, olfactory bulbus, an d cerebellum. Our results suggest that the GCS plays a major role in the fo rebrain and cerebellum rather than in the spinal cord, and that N-methyl-D- aspartate receptor may participate in neuropathogenesis of NKH. (C) 2001 El sevier Science BY All rights reserved.