Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson's disease.

IF 4.6 3区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Gene Therapy Pub Date : 2024-10-09 DOI:10.1038/s41434-024-00492-8
Piniel Alphayo Kambey, Jiao Wu, WenYa Liu, Mingyu Su, Wokuheleza Buberwa, Chuanxi Tang
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Abstract

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.

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在帕金森病小鼠模型中,靶向血清反应因子(SRF)可使ΔFosB失活并减轻左旋多巴诱发的运动障碍。
左旋-3,4-二羟基苯丙氨酸(L-DOPA)是目前治疗帕金森病(PD)的首选药物,被视为黄金标准。然而,患者长期使用左旋多巴会导致不自主运动,即左旋多巴诱发的运动障碍(LID),包括影响躯干、四肢和面部的无法控制的肌张力障碍。ΔFosB蛋白是FosB基因的一个截短剪接变体,它在LID中的作用已得到承认,但其潜在机制仍难以捉摸。在这里,我们使用一种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 的表达和左旋多巴诱导的运动障碍。Western 印迹分析表明,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,敲除 SRF 能显著减少异常不自主运动(AIMS)和ΔFosB 的表达。相反,SRF的过表达会导致ΔFosB表达增加,并加重左旋多巴诱导的运动障碍。为了揭示 Akt 信号通路在这一现象中的调控作用,我们通过腹腔注射 Akt 激动剂 SC79 给帕金森病小鼠模型,然后给予左旋多巴。与接受正常生理盐水的小鼠相比,SRF、ΔFosB和磷酸化Akt(p-Akt)的表达明显增加,这表明这些现象是通过Akt信号通路发生的。总之,我们的研究结果为解决左旋多巴诱发的运动障碍找到了一个很有前景的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Gene Therapy
Gene Therapy 医学-生化与分子生物学
CiteScore
9.70
自引率
2.00%
发文量
67
审稿时长
4-8 weeks
期刊介绍: Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.
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