QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 27, 2007, 27(26):6995-7005; doi:10.1523/JNEUROSCI.0852-07.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (19) Citing Articles via Google Scholar Google Scholar Articles by Santini, E. Articles by Fisone, G. Search for Related Content PubMed PubMed Citation Articles by Santini, E. Articles by Fisone, G.

 Previous Article  |  Next Article 

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

Emanuela Santini,¹ Emmanuel Valjent,^2,3,4 Alessandro Usiello,⁵ Manolo Carta,⁶ Anders Borgkvist,¹ Jean-Antoine Girault,^2,3,4 Denis Hervé,^2,3,4 Paul Greengard,⁷ and Gilberto Fisone^1,7

¹Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden, ²Inserm, Unité 839, 75005 Paris, France, ³Université Pierre et Marie Curie, 75005 Paris, France, ⁴Institut du Fer à Moulin, 75005 Paris, France, ⁵Centro di Ingegneria Genetica, Biotecnologie Avanzate, 80145 Naples, Italy, ⁶Wallenberg Neuroscience Centre, Lund University, 22184 Lund, Sweden, and ⁷Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021

Correspondence should be addressed to Gilberto Fisone, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden. Email: gilberto.fisone{at}ki.se

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 (-[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.

Key words: mouse; MSK-1; 6-OHDA; Parkinson's disease; SL327; striatum

---

Received Feb. 26, 2007; revised April 27, 2007; accepted May 15, 2007.

Correspondence should be addressed to Gilberto Fisone, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden. Email: gilberto.fisone{at}ki.se

This article has been cited by other articles:

				E. Klann Thwarting Dyskinesia by Targeting mTORC1 Sci. Signal., July 21, 2009; 2(80): pe42 - pe42. [Abstract] [Full Text] [PDF]

				E. Santini, M. Heiman, P. Greengard, E. Valjent, and G. Fisone Inhibition of mTOR Signaling in Parkinson's Disease Prevents L-DOPA-Induced Dyskinesia Sci. Signal., July 21, 2009; 2(80): ra36 - ra36. [Abstract] [Full Text] [PDF]

				A. Pisani and J. Shen Levodopa-induced dyskinesia and striatal signaling pathways PNAS, March 3, 2009; 106(9): 2973 - 2974. [Full Text] [PDF]

				J. R. Crittenden, I. Cantuti-Castelvetri, E. Saka, C. E. Keller-McGandy, L. F. Hernandez, L. R. Kett, A. B. Young, D. G. Standaert, and A. M. Graybiel Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy PNAS, February 24, 2009; 106(8): 2892 - 2896. [Abstract] [Full Text] [PDF]

				K. B. Dupre A Potential Neuroanatomical Dissociation of DARPP-32 in Striatal ERK Signaling J. Neurosci., October 22, 2008; 28(43): 10783 - 10785. [Full Text] [PDF]

				J. Bertran-Gonzalez, C. Bosch, M. Maroteaux, M. Matamales, D. Herve, E. Valjent, and J.-A. Girault Opposing Patterns of Signaling Activation in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons in Response to Cocaine and Haloperidol J. Neurosci., May 28, 2008; 28(22): 5671 - 5685. [Abstract] [Full Text] [PDF]

				X. Zhang, P. E. Andren, P. Greengard, and P. Svenningsson Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism PNAS, February 12, 2008; 105(6): 2163 - 2168. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help