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The Journal of Neuroscience, August 8, 2007, 27(32):8475-8485; doi:10.1523/JNEUROSCI.0792-07.2007

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Cellular/Molecular
Neurite Degeneration Induced by Heme Deficiency Mediated via Inhibition of NMDA Receptor-Dependent Extracellular Signal-Regulated Kinase 1/2 Activation

Tatyana Chernova, Joern R. Steinert, Christopher J. Guerin, Pierluigi Nicotera, Ian D. Forsythe, and Andrew G. Smith

Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester LE1 9HN, United Kingdom

Correspondence should be addressed to Tatyana Chernova, Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK. Email: tc28{at}le.ac.uk

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.

Key words: neurodegeneration; heme; ERK pathway; NMDA receptor; patch clamp; neuron

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Received Feb. 21, 2007; revised June 8, 2007; accepted June 11, 2007.

Correspondence should be addressed to Tatyana Chernova, Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK. Email: tc28{at}le.ac.uk

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