Scholarlink

<p>Childhood-onset DYT1 dystonia is a severe movement disorder caused by a heterozygous ΔE mutation in <i>TOR1A</i>, yet the molecular mechanisms driving disease remain unclear. The nuclear lamina, a key structural scaffold for nuclear integrity and gene regulation, has emerged as a potential site of dysfunction. Here, we investigated the role of nuclear Lamin B1 dysregulation in DYT1 pathology using patient fibroblasts and human iPSC-derived neurons. We show that excess Lamin B1 thickens the nuclear lamina, distorts nuclear architecture, and impairs nucleocytoplasmic transport. Proteomic profiling further revealed that dysregulated Lamin B1 disrupts neuronal signaling pathways, with 14-3-3 proteins, highly abundant chaperones essential for neuronal development and homeostasis, being the most affected. Functional studies demonstrated that loss of 14-3-3 proteins compromises neuron differentiation, whereas restoring their levels rescues DYT1 neuronal defects by correcting Lamin B1 mislocalization. These findings establish a mechanistic link between nuclear architecture, intracellular signaling, and neuronal deficits in DYT1 dystonia, and identify Lamin B1 and 14-3-3 proteins as promising therapeutic targets with broader relevance to neurological disease.</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

Dysregulated nuclear Lamin B1 in DYT1 dystonia thickens nuclear lamina and disrupts 14-3-3 proteins

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月15日

查看全文
  • Yuntian Duan,
  • Masood Sepehrimanesh,
  • Md Abir Hosain,
  • Haochen Cui,
  • Jacob Stagray,
  • Xinggui Shen,
  • Ying Xiao,
  • Yuqing Li,
  • Chun-Li Zhang,
  • Baojin Ding

摘要

Childhood-onset DYT1 dystonia is a severe movement disorder caused by a heterozygous ΔE mutation in TOR1A, yet the molecular mechanisms driving disease remain unclear. The nuclear lamina, a key structural scaffold for nuclear integrity and gene regulation, has emerged as a potential site of dysfunction. Here, we investigated the role of nuclear Lamin B1 dysregulation in DYT1 pathology using patient fibroblasts and human iPSC-derived neurons. We show that excess Lamin B1 thickens the nuclear lamina, distorts nuclear architecture, and impairs nucleocytoplasmic transport. Proteomic profiling further revealed that dysregulated Lamin B1 disrupts neuronal signaling pathways, with 14-3-3 proteins, highly abundant chaperones essential for neuronal development and homeostasis, being the most affected. Functional studies demonstrated that loss of 14-3-3 proteins compromises neuron differentiation, whereas restoring their levels rescues DYT1 neuronal defects by correcting Lamin B1 mislocalization. These findings establish a mechanistic link between nuclear architecture, intracellular signaling, and neuronal deficits in DYT1 dystonia, and identify Lamin B1 and 14-3-3 proteins as promising therapeutic targets with broader relevance to neurological disease.