Scholarlink

<p>Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of <i>Echs1</i> in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, <i>Echs1</i> deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator <i>Atf4</i>, acquire H3K9cr. <i>Atf4</i> then upregulates fatty acid synthase (<i>Fasn</i>), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting <i>Fasn</i> can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or <i>Atf4</i> inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an <i>Echs1</i>-H3K9cr-<i>Atf4</i>-<i>Fasn</i> axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.</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

Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月1日

查看全文
  • Chun-Hui Duan,
  • Pei-Pei Liu,
  • Xin Sun,
  • Wen-Hui Ma,
  • Jia-Ying Pang,
  • Zi-Han Zhang,
  • Xiao Li,
  • Lin-Fei Jiao,
  • Hong-Zhen Du,
  • Zhao-Qian Teng,
  • Hou-Zao Chen,
  • Chang-Mei Liu

摘要

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of Echs1 in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, Echs1 deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator Atf4, acquire H3K9cr. Atf4 then upregulates fatty acid synthase (Fasn), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting Fasn can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or Atf4 inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an Echs1-H3K9cr-Atf4-Fasn axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.