Scholarlink

<p>Neuronal intranuclear inclusion disease is caused by abnormal GGC repeat expansion in the NOTCH2NLC gene, though its pathogenic mechanism remains incompletely understood. This study shows that the abnormally expanded polyG-uN2C protein, encoded by the repeat sequence, contains intrinsically disordered regions and forms aggregates, leading to mislocalization of nucleophosmin and downregulation of fibrillarin. PolyG aggregates interact with nucleophosmin and rRNA, disrupting ribosomal homeostasis. Furthermore, polyG facilitates the downregulation of chromatin structural proteins CTCF and RAD21, thereby impairing chromatin organization. This pathological manifestation can be mitigated by restoring CTCF/RAD21 expression. Furthermore, in brain organoids derived from neuronal intranuclear inclusion disease patients, we observe nucleolar stress accompanied by genome-wide chromatin structural alterations. These changes correlate with increased DNA damage and cellular senescence phenotypes. Notably, antisense oligonucleotides targeting GGC effectively reduce polyG aggregation and ameliorate related molecular defects, ultimately alleviating senescence-associated phenotypes. These findings establish key mechanisms underlying neuronal intranuclear inclusion disease pathogenesis and provide proof-of-concept for targeted therapy.</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

ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

查看全文
  • Mengjie Li,
  • Mibo Tang,
  • Xiaoyan Hao,
  • Zhengwei Hu,
  • Dongrui Ma,
  • Shuangjie Li,
  • Chunyan Zuo,
  • Zhiyun Wang,
  • Yuanyuan Liang,
  • Yanmei Feng,
  • Chenwei Hao,
  • Chen Wang,
  • Huanyu Li,
  • Yalan Yang,
  • Yuemeng Sun,
  • Shasha Qi,
  • Chengyuan Mao,
  • Yuming Xu,
  • Qun Wang,
  • De Yang,
  • Ruwei Yang,
  • Ziyao Zhou,
  • Peilin Ji,
  • Song Tan,
  • Zaiqiang Zhang,
  • Hao Chen,
  • Albert R. La Spada,
  • Changhe Shi

摘要

Neuronal intranuclear inclusion disease is caused by abnormal GGC repeat expansion in the NOTCH2NLC gene, though its pathogenic mechanism remains incompletely understood. This study shows that the abnormally expanded polyG-uN2C protein, encoded by the repeat sequence, contains intrinsically disordered regions and forms aggregates, leading to mislocalization of nucleophosmin and downregulation of fibrillarin. PolyG aggregates interact with nucleophosmin and rRNA, disrupting ribosomal homeostasis. Furthermore, polyG facilitates the downregulation of chromatin structural proteins CTCF and RAD21, thereby impairing chromatin organization. This pathological manifestation can be mitigated by restoring CTCF/RAD21 expression. Furthermore, in brain organoids derived from neuronal intranuclear inclusion disease patients, we observe nucleolar stress accompanied by genome-wide chromatin structural alterations. These changes correlate with increased DNA damage and cellular senescence phenotypes. Notably, antisense oligonucleotides targeting GGC effectively reduce polyG aggregation and ameliorate related molecular defects, ultimately alleviating senescence-associated phenotypes. These findings establish key mechanisms underlying neuronal intranuclear inclusion disease pathogenesis and provide proof-of-concept for targeted therapy.