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Wednesday, December 3, 2008

Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signaling
PNAS
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.


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