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Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia

Santini, Emanuela; Valjent, Emmanuel; Usiello, Alessandro; Carta, Manolo LU ; Borgkvist, Anders; Girault, Jean-Antoine; Herve, Denis; Greengard, Paul and Fisone, Gilberto (2007) In Journal of Neuroscience 27(26). p.6995-7005
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
striatum, SL327, Parkinson's disease, 6-OHDA, mouse, MSK-1
in
Journal of Neuroscience
volume
27
issue
26
pages
6995 - 7005
publisher
Society for Neuroscience
external identifiers
  • wos:000247619600015
  • scopus:34347357671
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0852-07.2007
language
English
LU publication?
yes
id
10c55b9b-622b-4b46-84c4-fb825452aa52 (old id 647684)
date added to LUP
2007-12-04 14:59:46
date last changed
2017-11-05 04:34:08
@article{10c55b9b-622b-4b46-84c4-fb825452aa52,
  abstract     = {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.},
  author       = {Santini, Emanuela and Valjent, Emmanuel and Usiello, Alessandro and Carta, Manolo and Borgkvist, Anders and Girault, Jean-Antoine and Herve, Denis and Greengard, Paul and Fisone, Gilberto},
  issn         = {1529-2401},
  keyword      = {striatum,SL327,Parkinson's disease,6-OHDA,mouse,MSK-1},
  language     = {eng},
  number       = {26},
  pages        = {6995--7005},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0852-07.2007},
  volume       = {27},
  year         = {2007},
}