Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia.
The molecular basis of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), one of the major hindrances in the current therapy for Parkinson's disease, is still unclear. We show that attenuation of cAMP signaling in the medium spiny neurons of the striatum, achieved by genetic inactivation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), reduces LID. We also 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 involved in transcriptional regulation. In line with these observations, we found that c-Fos expression is abnormally elevated in the striata of mice affected by LID. Persistent enhancement of the ERK signaling cascade is implicated in the generation of LID. Thus, pharmacological inactivation of ERK1/2 achieved using SL327 (alpha-[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 striatal medium spiny neurons of a signaling pathway including sequential phosphorylation of DARPP-32, ERK1/2, MSK-1, and histone H3.
Santini
Emanuela
E
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
Valjent
Emmanuel
E
Usiello
Alessandro
A
Carta
Manolo
M
Borgkvist
Anders
A
Girault
Jean-Antoine
JA
Hervé
Denis
D
Greengard
Paul
P
Fisone
Gilberto
G
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000009:adverse effects; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016627:Oxidopamine; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D000242:Cyclic AMP; D018491:Dopamine Agonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D048049:Extracellular Signal-Regulated MAP Kinases; D006657:Histones; D007980:Levodopa; D016627:Oxidopamine; D018091:Receptors, AMPA; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C497929:Ppp1r1b protein, mouse; C116919:mitogen and stress-activated protein kinase 1