Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signaling
Abstract
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 (IC50 = 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.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- December 2008
- DOI:
- 10.1073/pnas.0807758105
- Bibcode:
- 2008PNAS..10519962C
- Keywords:
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- cerebellum;
- Crk-associated substrate;
- fetal alcohol spectrum disorders;
- Fyn kinase;
- Biological Sciences:Neuroscience