Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou Science Park, Huangpu District, Guangzhou, China.
Gene Ther. 2024 Nov;31(11-12):614-624. doi: 10.1038/s41434-024-00492-8. Epub 2024 Oct 9.
L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the preferred treatment for Parkinson's Disease (PD) and is considered the gold standard. However, prolonged use of L-DOPA in patients can result in involuntary movements known as Levodopa-induced dyskinesia (LID), which includes uncontrollable dystonia affecting the trunk, limbs, and face. The role of ΔFosB protein, a truncated splice variant of the FosB gene, in LID has been acknowledged, but its underlying mechanism has remained elusive. Here, using a mouse model of Parkinson's disease treated with chronic levodopa we demonstrate that serum response factor (SRF) binds to the FosB promoter, thereby activating FosB expression and levodopa induced-dyskinetic movements. Western blot analysis demonstrates a significant increase in SRF expression in the dyskinetic group compared to the control group. Knocking down SRF significantly reduced abnormal involuntary movements (AIMS) and ΔFosB expression compared to the control. Conversely, overexpression of SRF led to an increase in ΔFosB expression and worsened levodopa-induced dyskinesia. To shed light on the regulatory role of the Akt signaling pathway in this phenomenon, we administered the Akt agonist SC79 to PD mouse models via intraperitoneal injection, followed by L-DOPA administration. The expression of SRF, ΔFosB, and phosphorylated Akt (p-Akt) significantly increased in this group compared to the group receiving normal saline to signify that these happen through Akt signaling pathway. Collectively, our findings identify a promising therapeutic target for addressing levodopa-induced dyskinesia.
L-3,4-二羟苯丙氨酸（L-DOPA）是目前治疗帕金森病（PD）的首选药物，被认为是金标准。然而，患者长期使用 L-DOPA 会导致不自主运动，称为左旋多巴诱导的运动障碍（LID），包括影响躯干、四肢和面部的无法控制的肌张力障碍。ΔFosB 蛋白（FosB 基因的截短剪接变体）在 LID 中的作用已得到认可，但其潜在机制仍不清楚。在这里，我们使用慢性左旋多巴治疗的帕金森病小鼠模型证明，血清反应因子（SRF）与 FosB 启动子结合，从而激活 FosB 表达和左旋多巴诱导的运动障碍。Western blot 分析表明，与对照组相比，运动障碍组的 SRF 表达显著增加。与对照组相比，敲低 SRF 可显著减少异常不自主运动（AIMS）和 ΔFosB 表达。相反，SRF 的过表达导致 ΔFosB 表达增加，并使左旋多巴诱导的运动障碍恶化。为了阐明 Akt 信号通路在这一现象中的调节作用，我们通过腹腔注射向 PD 小鼠模型给予 Akt 激动剂 SC79，然后给予 L-DOPA。与接受生理盐水的组相比，该组的 SRF、ΔFosB 和磷酸化 Akt（p-Akt）的表达显著增加，表明这些变化是通过 Akt 信号通路发生的。总之，我们的研究结果确定了一个有前途的治疗靶点，用于解决左旋多巴诱导的运动障碍。
