Herman Wolosker, MD, PhD
Professor of Biochemistry
MD, 1993 - Federal University of Rio de Janeiro, Brazil
PhD, 1996 - Federal University of Rio de Janeiro, Brazil
Unconventional transmitters and neurodegeneration
Research in my laboratory focuses on understanding the roles of unconventional neurotransmitters, like the D-amino acids in the central nervous system. We are particularly interested in the regulation of N-Methyl- D-aspartate receptors (NMDARs) by D-serine, a D-enantiomer previously thought to be restricted to bacteria or lower invertebrates. D-Serine is now increasingly appreciated as a major physiologic ligand for NMDARs that mediates NMDAR synaptic responses and neurotoxicity both in vitro and in vivo. In addition to neurotransmission, NMDARs play a key role in neurodegeneration, with their excessive activation contributing to neuronal death in several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Over the past few years, we have elucidated the mechanisms of D-serine synthesis by the enzyme serine racemase and discovered novel pathways regulating D-serine production and release from neural cells. We discovered that D-serine is the dominant NMDAR co-agonist mediating neurotoxicity, raising the possibility that drugs that curb D-serine synthesis or release might be useful in neurodegenerative diseases involving NMDAR over-stimulation.
Another research goal is to discover novel metabolic pathways controlling neurotransmission and glia-neuron cross-talk. We recently identified new molecular components of the serine shuttle, a metabolic pathway that controls neuronal synthesis of D-serine and glycine and appears to be required for both excitatory and inhibitory neurotransmission.
My laboratory employs biochemistry, cell biology, behavior and electrophysiology approaches to study new mice knockout models. These models will allow the identification of novel pathways that participate in glia-neuron cross-talk and neurodegenerative processes.
Safory H, Neame S, ShulmanY, Zubedat S, Radzishevsky I, Rosenberg D, Sason H, Engelender S, Avital A, Hülsmann S, Schiller J and Wolosker H. 2015. The alanine-serine-cysteine-1 (Asc-1) transporter is a regulator of glycine metabolism and glycinergic inhibitory transmission. EMBO Rep. 16, 590-8.
Le Bail M, Sacchi S, Yatsenko N, Martineau M, Radzishevsky I, Conrod S, Ouares KA, Wolosker H, Pollegioni L, Billard JM, Mothet JP. 2015. The identity of the NMDA receptor co-agonist is synapse specific and developmentally regulated in the hippocampus. Proc. Natl. Acad. Sci. USA 112, E204-13.
Dikopoltsev E, Foltyn VN, Zehl M, Jensen ON, Mori H, Radzishevsky I, and Wolosker H. 2014. FBXO22 is required for optimal synthesis of the NMDA receptor co-agonist D-Serine J. Biol. Chem. 289, 33904-15.
Rosenberg D, Artoul S, Segal AC, Kolodney G, Dikopoltsev E, Radzishevsky I, Foltyn VN, Inoue R, Mori H, Billard JM, and Wolosker H. 2013. Neuronal D-serine and glycine release through the Asc-1 transporter regulates NMDAR-dependent synaptic activity. J. Neurosci. 33, 3533-3544.
Ehmsen JT, Ma TM, Sason H, Rosenberg D, Ogo T, Furuya S, Snyder SH, and Wolosker H. 2013. D-Serine in Glia and Neurons Derives from 3-Phosphoglycerate Dehydrogenase. J. Neurosci. 33, 12464-12469.
The serine shuttle model.
Astrocytes obtain glucose from the blood via glucose transporters (Glut1) and convert it to L-serine via the "phosphorylated pathway", which depends on the 3-phosphoglycerate dehydrogenase enzyme (Phgdh). Subsequently, L-serine shuttles to neurons via still unidentified neutral amino acid transporters, and fuels the synthesis of D-serine and glycine by neurons. Neuronal D-serine release via the Asc-1 transporter or depolarization-sensitive pathways appears to regulate NMDARs. To a lesser extent, D-serine may come from glia, since only a small fraction of astrocytes contain relatively low levels of serine racemase (SR). Adapted from Radzishevsky and Wolosker, Biochem. Soc. Trans. (2013) 41, 1546–1550.