Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes

Neurobiol Dis. 2010 Feb;37(2):423-33. doi: 10.1016/j.nbd.2009.10.022. Epub 2009 Oct 29.


AGAT and GAMT, the two enzymes of the creatine synthesis pathway, are well expressed within CNS, suggesting autonomous brain creatine synthesis. This contradicts SLC6A8 deficiency, which causes creatine deficiency despite CNS expression of AGAT and GAMT. We hypothesized that AGAT and GAMT were not co-expressed by brain cells, and that guanidinoacetate must be transported between cells to allow creatine synthesis. We finely analyzed the cell-to-cell co-expression of AGAT, GAMT and SLC6A8 in various regions of rat CNS, and showed that in most structures, cells co-expressing AGAT+GAMT (equipped for autonomous creatine synthesis) were in low proportions (<20%). Using reaggregating brain cell cultures, we also showed that brain cells take up guanidinoacetate and convert it to creatine. Guanidinoacetate uptake was competed by creatine. This suggests that in most brain regions, guanidinoacetate is transported from AGAT- to GAMT-expressing cells through SLC6A8 to allow creatine synthesis, thereby explaining creatine deficiency in SLC6A8-deficient CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidinotransferases / genetics
  • Amidinotransferases / metabolism
  • Animals
  • Brain Diseases, Metabolic, Inborn / metabolism*
  • Brain Diseases, Metabolic, Inborn / pathology
  • Brain Diseases, Metabolic, Inborn / physiopathology
  • Brain Mapping
  • Cell Count
  • Cells, Cultured
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • Central Nervous System / physiopathology
  • Creatine / biosynthesis
  • Creatine / deficiency*
  • Glycine / analogs & derivatives
  • Glycine / metabolism
  • Guanidinoacetate N-Methyltransferase / genetics
  • Guanidinoacetate N-Methyltransferase / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Neurons / pathology
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics
  • Plasma Membrane Neurotransmitter Transport Proteins / metabolism*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Syndrome


  • Nerve Tissue Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • RNA, Messenger
  • Slc6a8 protein, rat
  • Gamt protein, rat
  • Guanidinoacetate N-Methyltransferase
  • Amidinotransferases
  • glycine amidinotransferase
  • glycocyamine
  • Creatine
  • Glycine