Neurobiology of Disease Critical Involvement of cAMP/DARPP-32 and Extracellular Signal-Regulated Protein Kinase Signaling in

The molecular basis of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), one of the major hindrances in the current therapy forParkinson’sdisease, is still unclear.Weshow that attenuationof cAMPsignaling in themediumspinyneuronsof the striatum, achievedbygenetic inactivationof thedopamineandcAMP-regulatedphosphoproteinof 32kDa (DARPP-32), reducesLID.Wealso show that, in dyskinetic mice, sensitized cAMP/cAMP-dependent protein kinase/DARPP-32 signaling leads to phosphorylation/activation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). The increase in ERK1/2 phosphorylation associated with dyskinesia results in activation of mitogen- and stress-activated kinase-1 (MSK-1) and phosphorylation of histone H3, two downstream targets of ERK involvedintranscriptionalregulation.Inlinewiththeseobservations,wefoundthatc-Fosexpressionisabnormallyelevatedinthestriataofmice affectedbyLID.Persistentenhancementof theERKsignalingcascade is implicated in thegenerationofLID.Thus,pharmacological inactivation of ERK1/2 achieved using SL327 (-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile), an inhibitor of the mitogen-activated kinase/ERK kinase, MEK, during chronic L-DOPA treatment counteracts the induction dyskinesia. Together, these results indicate that a significant proportion of the abnormal involuntary movements developed in response to chronic L-DOPA are attributable to hyperactivation in striatalmedium spiny neurons of a signaling pathway including sequential phosphorylation ofDARPP-32, ERK1/2,MSK-1, and histoneH3