Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures

IF 12.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2025-06-02 DOI:10.1038/s41589-025-01920-5

Longze Sha, Yanbing Wang, Peixin Meng, Yu Deng, Ting Chen, Xiuneng Zhang, Yousong Ye, Qi Xu

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Abstract

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy. Lowering the levels of N-methyl-d-aspartate receptor (NMDAR) ligands has been suggested as a promising therapeutic strategy for TLE. d-Serine gates synaptic NMDARs in the hippocampus but the effect of d-serine on seizure activity remains poorly understood. Here, we show that serine levels in the hippocampus were increased in persons with TLE and in a mouse model of TLE. Eliminating d-serine or blocking its binding with NMDARs suppressed seizures in mouse models. Astrocyte-derived l-serine was found to regulate interstitial d-serine levels and seizure activity through a process controlled by phosphoserine phosphatase (PSPH). We identified a potent PSPH inhibitor, Z218484536, and found that its systemic administration reduced spontaneous epileptic discharges in mouse and cynomolgus monkey models of TLE. Overall, these results indicate that PSPH is a promising therapeutic target for TLE and support further preclinical studies of Z218484536.

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药物抑制PSPH可降低丝氨酸水平和癫痫发作

颞叶癫痫（TLE）是最常见的耐药癫痫类型。降低n -甲基-d-天冬氨酸受体（NMDAR）配体的水平被认为是治疗TLE的一种有前景的策略。d-丝氨酸抑制海马突触NMDARs，但d-丝氨酸对癫痫发作活动的影响尚不清楚。在这里，我们发现海马丝氨酸水平在TLE患者和TLE小鼠模型中增加。在小鼠模型中，消除d-丝氨酸或阻断其与NMDARs的结合可抑制癫痫发作。星形胶质细胞衍生的l-丝氨酸通过磷酸化丝氨酸磷酸酶（PSPH）控制的过程调节间质d-丝氨酸水平和癫痫发作活动。我们鉴定了一种有效的PSPH抑制剂Z218484536，并发现其全身给药可减少小鼠和食食猴TLE模型的自发性癫痫放电。综上所述，这些结果表明PSPH是TLE的一个有希望的治疗靶点，并为Z218484536的进一步临床前研究提供了支持。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.