Phosphodiesterase inhibition and Gucy2C activation enhance tyrosine hydroxylase Ser40 phosphorylation and improve 6-hydroxydopamine-induced motor deficits.

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell and Bioscience Pub Date : 2024-10-25 DOI:10.1186/s13578-024-01312-7
Erik H Douma, Jesse Stoop, Matthijs V R Lingl, Marten P Smidt, Lars P van der Heide
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引用次数: 0

Abstract

Background: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the nigrostriatal pathway, leading to dopamine deficiency and motor impairments. Current treatments, such as L-DOPA, provide symptomatic relief but result in off-target effects and diminished efficacy over time. This study explores an alternative approach by investigating the activation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Specifically, we explore the effects of phosphodiesterase (PDE) inhibition and guanylate cyclase-C (GUCY2C) activation on tyrosine hydroxylase Ser40 phosphorylation and their impact on motor behavior in a 6-hydroxydopamine (6-OHDA) Parkinson's disease model.

Results: Our findings demonstrate that increasing cyclic nucleotide levels through PDE inhibition and GUCY2C activation significantly enhances tyrosine hydroxylase Ser40 phosphorylation. In a Pitx3-deficient mouse model, which mimics the loss of dopaminergic neurons seen in Parkinson's disease, Ser40 phosphorylation remained manipulable despite reduced tyrosine hydroxylase protein levels. Moreover, we observed no evidence of tyrosine hydroxylase degradation due to Ser40 phosphorylation, challenging previous reports. Furthermore, both PDE inhibition and GUCY2C activation resulted in improved motor behavior in the 6-OHDA Parkinson's disease mouse model, highlighting the potential therapeutic benefits of these approaches.

Conclusions: This study underscores the therapeutic potential of enhancing tyrosine hydroxylase Ser40 phosphorylation to improve motor function in Parkinson's disease. Both PDE inhibition and GUCY2C activation represent promising non-invasive strategies to modulate endogenous dopamine biosynthesis and address motor deficits. These findings suggest that targeting cyclic nucleotide pathways could lead to novel therapeutic approaches, either as standalone treatments or in combination with existing therapies like L-DOPA, aiming to provide more durable symptom relief and potentially mitigate neurodegeneration in Parkinson's disease.

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磷酸二酯酶抑制和 Gucy2C 激活可增强酪氨酸羟化酶 Ser40 磷酸化,改善 6-羟基多巴胺诱导的运动障碍。
背景:帕金森病的特征是黑质通路中多巴胺能神经元的逐渐丧失,导致多巴胺缺乏和运动障碍。目前的治疗方法,如左旋多巴可缓解症状,但会产生脱靶效应,且疗效会随着时间的推移而减弱。本研究通过研究多巴胺合成过程中的限速酶--酪氨酸羟化酶的激活,探索了另一种方法。具体来说,我们探讨了磷酸二酯酶(PDE)抑制和鸟苷酸环化酶-C(GUCY2C)激活对酪氨酸羟化酶Ser40磷酸化的影响及其对6-羟基多巴胺(6-OHDA)帕金森病模型运动行为的影响:我们的研究结果表明,通过抑制PDE和激活GUCY2C来提高环核苷酸水平可显著增强酪氨酸羟化酶Ser40磷酸化。在模拟帕金森病多巴胺能神经元缺失的 Pitx3 缺失小鼠模型中,尽管酪氨酸羟化酶蛋白水平降低,但 Ser40 磷酸化仍可操控。此外,我们没有观察到 Ser40 磷酸化导致酪氨酸羟化酶降解的证据,这对之前的报道提出了质疑。此外,PDE抑制和GUCY2C激活都能改善6-OHDA帕金森病小鼠模型的运动行为,突出了这些方法的潜在治疗效果:本研究强调了增强酪氨酸羟化酶Ser40磷酸化以改善帕金森病运动功能的治疗潜力。PDE抑制和GUCY2C激活都是调节内源性多巴胺生物合成和解决运动障碍的有前途的非侵入性策略。这些研究结果表明,以环核苷酸通路为靶点可能会产生新的治疗方法,既可以作为独立疗法,也可以与 L-DOPA 等现有疗法相结合,从而提供更持久的症状缓解,并有可能减轻帕金森病的神经变性。
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
Cell and Bioscience
Cell and Bioscience BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
10.70
自引率
0.00%
发文量
187
审稿时长
>12 weeks
期刊介绍: Cell and Bioscience, the official journal of the Society of Chinese Bioscientists in America, is an open access, peer-reviewed journal that encompasses all areas of life science research.
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