Journal of Neuroscience, Год журнала: 2007, Номер 27(26), С. 6995 - 7005

Опубликована: Июнь 27, 2007

The molecular basis of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), one the major hindrances in current therapy for Parkinson9s disease, is still unclear. We show that attenuation cAMP signaling medium spiny neurons striatum, achieved by genetic inactivation dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32), reduces LID. also that, dyskinetic mice, sensitized cAMP/cAMP-dependent protein kinase/DARPP-32 leads to phosphorylation/activation extracellular signal-regulated kinases 1 2 (ERK1/2). increase ERK1/2 phosphorylation associated with results activation mitogen- stress-activated kinase-1 (MSK-1) histone H3, two downstream targets ERK involved transcriptional regulation. In line these observations, we found c-Fos expression abnormally elevated striata mice affected Persistent enhancement cascade implicated generation Thus, pharmacological using SL327 (α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile), an inhibitor mitogen-activated kinase/ERK kinase, MEK, during chronic l-DOPA treatment counteracts induction dyskinesia. Together, indicate a significant proportion abnormal involuntary movements developed response are attributable hyperactivation striatal pathway including sequential DARPP-32, ERK1/2, MSK-1, H3.

Язык: Английский