Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia
Author(s)Heiman, Myriam; Heilbut, Adrian; Francardo, Veronica; Kulicke, Ruth; Fenster, Robert; Kolaczyk, Eric D.; Mesirov, Jill P.; Surmeier, Dalton J.; Cenci, M. Angela; Greengard, Paul; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
Heiman, M., A. Heilbut, V. Francardo, R. Kulicke, R. J. Fenster, E. D. Kolaczyk, J. P. Mesirov, D. J. Surmeier, M. A. Cenci, and P. Greengard. “Molecular Adaptations of Striatal Spiny Projection Neurons During Levodopa-Induced Dyskinesia.” Proceedings of the National Academy of Sciences 111, no. 12 (March 5, 2014): 4578–4583.
Final published version