Neurite degeneration induced by heme deficiency mediated via inhibition of NMDA receptor-dependent extracellular signal-regulated kinase 1/2 activation.
The early stages of many neurodegenerative diseases and age-related degeneration are characterized by neurite damage and compromised synaptic function that precede neuronal cell death. We investigated the signaling mechanisms underlying neurite degeneration using cortical neuron cultures. Inhibition of heme synthesis caused neurite damage, without neuronal death, and was mediated by reduced NMDA receptor (NMDAR) expression and phosphorylation. The signaling toward the degenerative phenotype involved suppression of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and electrophysiological recording showed that the neurodegeneration is accompanied by reduced NMDAR current and Ca2+ influx, as well as reduced voltage-gated sodium currents, consistent with compromised neurite integrity. Rescue from the degenerative phenotype by heme replacement was dependent on restoration of NR2B subunit phosphorylation and expression of NMDAR currents with higher Ca2+ permeability, consistent with triggering prosurvival ERK1/2 signaling to maintain and extend neurites. This study demonstrated a new mechanism of neurodegeneration in which impaired heme synthesis led to NMDAR signaling dysfunction, suppression of the prosurvival ERK1/2 pathway, and progressive fragmentation of neuronal projections.
Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester LE1 9HN, United Kingdom. tc28@le.ac.uk
Tatyana
T
Chernova
Joern R
JR
Steinert
Christopher J
CJ
Guerin
Pierluigi
P
Nicotera
Ian D
ID
Forsythe
Andrew G
AG
Smith
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D006418:Heme / Q000172:deficiency* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology; D016501:Neurites / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D006418:Heme; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3