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

Gene Therapy volume 31, pages 614–624 (2024)Cite this article

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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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Fig. 1: Parkinson’s disease mouse model.
Fig. 2: Levodopa-induced dyskinesia animal model and the chromatin immunoprecipitation results of SRF binding to FosB promoter.
Fig. 3: Expression of SRF is significantly elevated in a mouse model of levodopa-induced dyskinesia.
Fig. 4: Knocking down of SRF in mouse reduces ΔFosB expression and the Levodopa-induced dyskinetic movements.
Fig. 5: Overexpression of SRF in mouse increases the expression of ΔFosB and aggravate Levodopa-Induced Dyskinetic movements.
Fig. 6: SRF regulates the activity of ΔFosB through the Akt signaling pathway.

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Data availability

The data that support the findings of this study are available on request from the corresponding authors [PAK & TCX].

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Funding

This project was funded by Jiangsu Province Science Foundation for Youths (Grant No. BK20210903).

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Authors and Affiliations

  1. Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China

    Piniel Alphayo Kambey, Jiao Wu, WenYa Liu, Mingyu Su & Chuanxi Tang

  2. 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

    Piniel Alphayo Kambey

  3. Department of Neurology, The second affiliated hospital of Xi’an Jiaotong University, 710049, Xi’an, China

    Wokuheleza Buberwa

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  1. Piniel Alphayo Kambey
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Contributions

PAK and TCX conceived the idea, designed and supervised the study; WJ performed the experiments; LWY, MYS and WB performed data analysis.

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Correspondence to Piniel Alphayo Kambey or Chuanxi Tang.

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Laboratory animal care and use protocols approved by the Xuzhou Medical University’s institutional animal care and use committee. This study exclusively utilized mice, therefore consent to participate is not applicable.

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Kambey, P.A., Wu, J., Liu, W. et al. Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson’s disease. Gene Ther 31, 614–624 (2024). https://doi.org/10.1038/s41434-024-00492-8

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