Scholarlink

<p>Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (<i>PPM1D</i>) gene. Patients carrying <i>PPM1D</i> mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol&#xa0;and plateletcrit level. Experimental brain ischemia in <i>Ppm1d</i>-deficient (<i>Ppm1d</i><sup>−</sup><sup><i>/</i></sup><sup>−</sup>) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct <i>Ppm1d</i>-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from <i>Ppm1d</i><sup>−</sup><sup><i>/</i></sup><sup>−</sup> mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, <i>Ppm1d</i> deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Gain-of-function PPM1D mutations attenuate ischemic stroke

  • 期刊论文

  • 发表日期：

    2025年5月21日

查看全文
  • Wenyan He,
  • Yan Li,
  • Junwan Fan,
  • Yang Liu,
  • Meng Yuan,
  • Si Cheng,
  • Xinying Huang,
  • Bo Yan,
  • Zhuoran Zhang,
  • Yuwen Xiu,
  • Huimin Zhu,
  • Tian Lan,
  • Zhilin Chang,
  • Yong Jiang,
  • Hao Li,
  • Xia Meng,
  • Yilong Wang,
  • Luc Van Kaer,
  • Alexei Verkhratsky,
  • Yongjun Wang,
  • Fu-Dong Shi,
  • Wei-Na Jin

摘要

Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene. Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d−/−) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d−/− mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke.