Dynamic DNA Methylation Regulates Levodopa-Induced Dyskinesia.
Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (l-DOPA) exposure in Parkinson disease patients. LID is a consequence of sustained changes in the transcriptional behavior of striatal neurons following dopaminergic stimulation. In neurons, transcriptional regulation through dynamic DNA methylation has been shown pivotal to many long-term behavioral modifications; however, its role in LID has not yet been explored. Using a rodent model, we show LID development leads to the aberrant expression of DNA demethylating enzymes and locus-specific changes to DNA methylation at the promoter regions of genes aberrantly transcribed following l-DOPA treatment. Looking for dynamic DNA methylation in LID genome-wide, we used reduced representation bisulfite sequencing and found an extensive reorganization of the dorsal striatal methylome. LID development led to significant demethylation at many important regulatory areas of aberrantly transcribed genes. We used pharmacologic treatments that alter DNA methylation bidirectionally and found them able to modulate dyskinetic behaviors. Together, these findings demonstrate that l-DOPA induces widespread changes to striatal DNA methylation and that these modifications are required for the development and maintenance of LID.



Levodopa-induced dyskinesia (LID) develops after repeated levodopa (l-DOPA) exposure in Parkinson disease patients and remains one of the primary obstacles to effective treatment. LID behaviors are a consequence of striatal neuron sensitization due to sustained changes in transcriptional behavior; however, the mechanisms responsible for the long-term maintenance of this cellular priming remain uncertain. Regulation of dynamic DNA methylation has been shown pivotal to the maintenance of several long-term behavioral modifications, yet its role in LID has not yet been explored. In this work, we report a pivotal role for the reorganization of DNA methylation in the development of LID and show that modification of DNA methylation may be a novel therapeutic target for use in preventing or reversing dyskinetic behaviors.
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
David A
DA
Figge
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Karen L
KL
Eskow Jaunarajs
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294 dstandaert@uab.edu.
David G
0000-0003-2921-8348
DG
Standaert
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003342:Corpus Striatum / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D049308:Dioxygenases / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D010797:Phthalimides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D000097642:GADD45 Proteins
D000978:Antiparkinson Agents; D049308:Dioxygenases; D004298:Dopamine; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007980:Levodopa; D016627:Oxidopamine; D010797:Phthalimides; D014364:Tryptophan; D000097642:GADD45 Proteins; C503639:RG108
DNA methylation; dyskinesia; l-DOPA