Mammalian D‐cysteine: A novel regulator of neural progenitor cell proliferation

Abstract

D-amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D-cysteine in mammalian brain. D-cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D-cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D-cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D-cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D-cysteine inhibits AKT phosphorylation at Thr 308 and Ser 473 in NPCs. D-cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D-cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D-cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD). K E Y W O R D S chirality, D-amino acids, endogenous D-cysteine, MARCKS (myristoylated alanine-rich C kinase substrate), neural progenitor cells (NPC), racemization, serine racemase ABBREVIATIONS: CRAPome, (contaminant repository for affinity purification); IP-MS, (immunoprecipitation followed by mass spectrometry); MARCKS, (myristoylated alanine-rich C kinase substrate); MARCKSL1, (MARCKS Like 1); NPC, (neural progenitor cells); PKC, (protein kinase C); PSD, (phosphorylation site domain); SR, (Serine Racemase).

Thoughts on the role of endogenous D‐cysteine in neuronal function

“…[3] It would seem that high levels of D-cysteine are required for early brain development, and indeed Roychaudhuri and Snyder do an excellent job of laying out a hypothesis for how D-cysteine regulates cell proliferation by altering kinase signaling. [2]' However, the question remains as to whether endogenous D-cysteine plays a role in normal brain function. D-cysteine can be modified in several different ways, either by addition of an ethyl or methyl-ester to enhance membrane permeability, or by S-nitrosylation by nitric oxide synthase.…”

“…[ 1 ] It was due to this tight regulation that it was only recently discovered that D‐cysteine is endogenously produced in the brain by Serine Racemase (SR). [ 2 ] D‐cysteine levels are highest in prenatal brain and rapidly decline with age. [ 2 ] DAO expression is extremely low in prenatal brains of humans, and increases with age, rising significantly in the first 2 years of life.…”

“…[ 2 ] D‐cysteine levels are highest in prenatal brain and rapidly decline with age. [ 2 ] DAO expression is extremely low in prenatal brains of humans, and increases with age, rising significantly in the first 2 years of life. [ 3 ] It would seem that high levels of D‐cysteine are required for early brain development, and indeed Roychaudhuri and Snyder do an excellent job of laying out a hypothesis for how D‐cysteine regulates cell proliferation by altering kinase signaling.…”

“…[ 3 ] It would seem that high levels of D‐cysteine are required for early brain development, and indeed Roychaudhuri and Snyder do an excellent job of laying out a hypothesis for how D‐cysteine regulates cell proliferation by altering kinase signaling. [ 2 ]’ However, the question remains as to whether endogenous D‐cysteine plays a role in normal brain function.…”

“…Roychaudhuri and Snyder's measurements of D‐cysteine in the brain show a sharp decline with age, but these measurements are across all tissues. [ 2 ] The concept that this amino acid is endogenously created in the brain via SR and degraded via DAO/3MS hints at a continuing role in intracellular neuronal signaling. To study this, we would need to develop specific histochemical or immunohistochemical stains for D‐cysteine, allowing us to visualize its expression in the brain under normal conditions and a variety of conditions/disease states such as Alzheimer's disease, schizophrenia, and OIRD.…”