Figge David A, Eskow Jaunarajs Karen L, Standaert David G
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294
J Neurosci. 2016 Jun 15;36(24):6514-24. doi: 10.1523/JNEUROSCI.0683-16.2016.
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.
左旋多巴诱导的异动症（LID）是一种持续性行为敏化现象，在帕金森病患者反复接触左旋多巴（l-DOPA）后出现。LID是多巴胺能刺激后纹状体神经元转录行为持续变化的结果。在神经元中，通过动态DNA甲基化进行的转录调控已被证明对许多长期行为改变至关重要；然而，其在LID中的作用尚未得到探索。使用啮齿动物模型，我们发现LID的发展导致DNA去甲基化酶的异常表达以及l-DOPA处理后异常转录基因启动子区域DNA甲基化的位点特异性变化。为了在全基因组范围内寻找LID中的动态DNA甲基化，我们使用了简化代表性亚硫酸氢盐测序，发现背侧纹状体甲基化组发生了广泛重组。LID的发展导致许多异常转录基因的重要调控区域出现显著去甲基化。我们使用双向改变DNA甲基化的药物治疗，发现它们能够调节异动行为。总之，这些发现表明l-DOPA诱导纹状体DNA甲基化发生广泛变化，并且这些修饰是LID发展和维持所必需的。
左旋多巴诱导的异动症（LID）在帕金森病患者反复接触左旋多巴（l-DOPA）后出现，仍然是有效治疗的主要障碍之一。LID行为是纹状体神经元敏化的结果，这是由于转录行为的持续变化；然而，负责这种细胞致敏长期维持的机制仍不确定。动态DNA甲基化的调控已被证明对几种长期行为改变的维持至关重要，但其在LID中的作用尚未得到探索。在这项工作中，我们报告了DNA甲基化重组在LID发展中的关键作用，并表明DNA甲基化修饰可能是预防或逆转异动行为的新治疗靶点。
