Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signaling.
The mechanisms by which ethanol damages the developing and adult central nervous system (CNS) remain unclear. Activity-dependent neuroprotective protein (ADNP) is a glial protein that protects the CNS against a wide array of insults and is critical for CNS development. NAPVSIPQ (NAP), a potent active fragment of ADNP, potentiated axon outgrowth in cerebellar granule neurons by activating the sequential tyrosine phosphorylation of Fyn kinase and the scaffold protein Crk-associated substrate (Cas). Pharmacological inhibition of Fyn kinase or expression of a Fyn kinase siRNA abolished NAP-mediated axon outgrowth. Concentrations of ethanol attained after social drinking blocked NAP-mediated axon outgrowth (IC(50) = 17 mM) by inhibiting NAP activation of Fyn kinase and Cas. These findings identify a mechanism for ADNP regulation of glial-neuronal interactions in developing cerebellum and a pathogenesis of ethanol neurotoxicity.
Chen
Suzhen
S
VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132, USA.
Charness
Michael E
ME
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D050719:Crk-Associated Substrate Protein; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000431:Ethanol; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn