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Gene expression analyses identify narp contribution in the development of L-DOPA-induced dyskinesia

Charbonnier-Beaupel, Fanny; Malerbi, Marion; Alcacer, Cristina LU ; Tahiri, Khadija; Carpentier, Wassila; Wang, Chuansong; During, Matthew J.; Xu, Desheng; Worley, Paul F. and Girault, Jean-Antoine, et al. (2015) In Journal of Neuroscience 35(1). p.96-111
Abstract

In Parkinson’s disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by l-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0 - 6 h after treatment with l-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by l-DOPA. L-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor... (More)

In Parkinson’s disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by l-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0 - 6 h after treatment with l-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by l-DOPA. L-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with l-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after l-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating l-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by l-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID.

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Contribution to journal
publication status
published
keywords
L-DOPA-induced dyskinesia, Narp, Parkinson’s disease, Transcriptome
in
Journal of Neuroscience
volume
35
issue
1
pages
16 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:84920517665
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.5231-13.2015
language
English
LU publication?
no
id
f9a203c5-9284-4b5a-916e-3a71da82a909
date added to LUP
2017-02-14 16:08:27
date last changed
2017-08-13 05:04:16
@article{f9a203c5-9284-4b5a-916e-3a71da82a909,
  abstract     = {<p>In Parkinson’s disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by l-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0 - 6 h after treatment with l-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by l-DOPA. L-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with l-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after l-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating l-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by l-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID.</p>},
  author       = {Charbonnier-Beaupel, Fanny and Malerbi, Marion and Alcacer, Cristina and Tahiri, Khadija and Carpentier, Wassila and Wang, Chuansong and During, Matthew J. and Xu, Desheng and Worley, Paul F. and Girault, Jean-Antoine and Hervé, Denis and Corvol, Jean-Christophe},
  issn         = {0270-6474},
  keyword      = {L-DOPA-induced dyskinesia,Narp,Parkinson’s disease,Transcriptome},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {96--111},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Gene expression analyses identify narp contribution in the development of L-DOPA-induced dyskinesia},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.5231-13.2015},
  volume       = {35},
  year         = {2015},
}