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Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia

Heiman, Myriam; Heilbut, Adrian; Francardo, Veronica LU ; Kulicke, Ruth; Fenster, Robert J.; Kolaczyk, Eric D.; Mesirov, Jill P.; Surmeier, Dalton James; Cenci, M. Angela LU and Greengard, Paul (2014) In Proceedings of the National Academy of Sciences of the United States of America 111(12). p.4578-4583
Abstract

Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic... (More)

Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic adaptations involving several signaling modulators, activator protein-1-dependent gene expression remains highly dysregulated in direct pathway SPNs upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.

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Contribution to journal
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published
subject
in
Proceedings of the National Academy of Sciences of the United States of America
volume
111
issue
12
pages
6 pages
publisher
National Acad Sciences
external identifiers
  • scopus:84897010488
ISSN
0027-8424
DOI
10.1073/pnas.1401819111
language
English
LU publication?
no
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63290b0d-16b5-47ea-9334-a5ba986c63a0
date added to LUP
2017-04-24 11:41:23
date last changed
2017-06-11 05:15:40
@article{63290b0d-16b5-47ea-9334-a5ba986c63a0,
  abstract     = {<p>Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic adaptations involving several signaling modulators, activator protein-1-dependent gene expression remains highly dysregulated in direct pathway SPNs upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.</p>},
  author       = {Heiman, Myriam and Heilbut, Adrian and Francardo, Veronica and Kulicke, Ruth and Fenster, Robert J. and Kolaczyk, Eric D. and Mesirov, Jill P. and Surmeier, Dalton James and Cenci, M. Angela and Greengard, Paul},
  issn         = {0027-8424},
  language     = {eng},
  number       = {12},
  pages        = {4578--4583},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia},
  url          = {http://dx.doi.org/10.1073/pnas.1401819111},
  volume       = {111},
  year         = {2014},
}