Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.
Gene Ther. 2021 Dec;28(12):760-770. doi: 10.1038/s41434-021-00249-7. Epub 2021 Mar 11.
L-Dopa-induced dyskinesia (LID) is associated with the upregulation of striatal ∆FosB in animal models and patients with Parkinson's disease (PD). A mechanistic role of ∆FosB is suspected because its transgenic overexpression leads to the early appearance of LID in rodents and primates. This study in rodents is aimed at exploring the therapeutic potential of striatal ∆FosB gene suppression to control LID in patients with PD. To determine the effect of reducing striatal ∆FosB expression, we used RNAi gene knockdown in a rat model of PD and assessed abnormal involuntary movements (AIMs) in response to L-Dopa. Rats with dopamine depletion received striatal injections of rAAV-∆FosB shRNA or a control virus before exposure to chronic L-Dopa treatment. The development of AIMs during the entire L-Dopa treatment period was markedly inhibited by ∆FosB gene knockdown and its associated molecular changes. The antiparkinsonian action of L-Dopa was unchanged by ∆FosB gene knockdown. These results suggest a major role for ∆FosB in the development of LID and support exploring strategies to reduce striatal ∆FosB levels in patients with PD.
左旋多巴诱导的运动障碍（LID）与动物模型和帕金森病（PD）患者纹状体 ∆FosB 的上调有关。由于其转基因过表达导致啮齿动物和灵长类动物中 LID 的早期出现，因此怀疑 ∆FosB 具有机制作用。这项在啮齿动物中的研究旨在探索抑制纹状体 ∆FosB 基因表达以控制 PD 患者 LID 的治疗潜力。为了确定降低纹状体 ∆FosB 表达的效果，我们在 PD 大鼠模型中使用 RNAi 基因敲低，并评估对 L-Dopa 的异常不自主运动（AIMs）的反应。多巴胺耗竭的大鼠在暴露于慢性 L-Dopa 治疗之前接受了 rAAV-∆FosB shRNA 或对照病毒的纹状体注射。 ∆FosB 基因敲低及其相关分子变化显着抑制了 AIMs 在整个 L-Dopa 治疗期间的发展。 ∆FosB 基因敲低对 L-Dopa 的抗帕金森作用没有影响。这些结果表明 ∆FosB 在 LID 的发展中起主要作用，并支持探索降低 PD 患者纹状体 ∆FosB 水平的策略。
