Department of Pharmacology and Psychiatry, Vanderbilt University, Nashville, TN, 37232-8548, USA.
Acta Neuropathol. 2010 Nov;120(5):623-31. doi: 10.1007/s00401-010-0740-8. Epub 2010 Aug 26.
Prolonged treatment of Parkinson's disease (PD) with levodopa leads to disabling side effects collectively referred to as 'dyskinesias'. We hypothesized that bioenergetic function in the putamen might play a crucial role in the development of dyskinesias. To test this hypothesis, we used post mortem samples of the human putamen and applied real time-PCR approaches and gene expression microarrays. We found that mitochondrial DNA (mtDNA) levels are decreased in patients who have developed dyskinesias, and mtDNA damage is concomitantly increased. These pathologies were not observed in PD subjects without signs of dyskinesias. The group of nuclear mRNA transcripts coding for the proteins of the mitochondrial electron transfer chain was decreased in patients with dyskinesias to a larger extent than in patients who had not developed dyskinesias. To examine whether dopamine fluctuations affect mtDNA levels in dopaminoceptive neurons, rat striatal neurons in culture were repeatedly exposed to levodopa, dopamine or their metabolites. MtDNA levels were reduced after treatment with dopamine, but not after treatment with dopamine metabolites. Levodopa led to an increase in mtDNA levels. We conclude that mitochondrial susceptibility in the putamen plays a role in the development of dyskinesias.
左旋多巴治疗帕金森病 (PD) 时间过长会导致致残的副作用，统称为“运动障碍”。我们假设壳核中的生物能量功能可能在运动障碍的发展中起着关键作用。为了验证这一假设，我们使用了人类壳核的死后样本，并应用了实时 PCR 方法和基因表达微阵列。我们发现，患有运动障碍的患者的线粒体 DNA（mtDNA）水平降低，同时 mtDNA 损伤增加。在没有运动障碍迹象的 PD 患者中没有观察到这些病变。编码线粒体电子传递链蛋白的核 mRNA 转录本的组在有运动障碍的患者中比在没有发生运动障碍的患者中降低的程度更大。为了研究多巴胺波动是否会影响多巴胺能神经元中的 mtDNA 水平，我们在培养的大鼠纹状体神经元中反复暴露于左旋多巴、多巴胺或其代谢物。在用多巴胺处理后 mtDNA 水平降低，但在用多巴胺代谢物处理后没有降低。左旋多巴导致 mtDNA 水平增加。我们的结论是，壳核中的线粒体易感性在运动障碍的发展中起作用。
