lysosomal 蛋白质 CLN3 的损失触发了 c-Abl 依赖的 YAP1 亲细胞亡信号传递
Neuza Domingues1, Alessia Calcagni'2,3, Sofia Freire4
1Multidisciplinary Institute of Ageing, Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. neuza.domingues@uc.pt.
EMBO reports
|November 6, 2025
概括
由CLN3突变引起的Batten病涉及一种新的机制,其中CLN3损失会触发DNA损伤和c-Abl激活,导致YAP1介导的细胞死亡. 这一发现可能为巴顿病提供新的治疗策略.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 细胞生物学 细胞生物学
背景情况:
- 巴顿病是一种致命的神经退行性疾病,目前没有治疗方法.
- 在CLN3基因的突变是巴顿病的最常见的原因.
- 驱动CLN3损失相关病理的分子机制尚不清楚.
研究的目的:
- 阐明CLN3损失影响细胞信号传递的分子机制.
- 为了确定参与巴顿病的病变发生的关键分子参与者.
- 探索巴顿病的潜在治疗点.
主要方法:
- 生成的人类CLN3淘汰 (CLN3-KO) 细胞.
- 在CLN3-KO细胞上进行RNA测序 (RNA-seq) 分析.
- 在视网膜色素上皮细胞和Cln3Δ7/8小鼠模型中研究了CLN3损失的影响.
主要成果:
- 转录分析发现YAP1是CLN3-KO细胞中的关键调节者.
- 在各种细胞类型和组织中,CLN3损失增加了YAP1介导的亲细胞亡信号.
- 缺少CLN3会导致DNA损伤,激活c-Abl激酶,该激酶可酸化YAP1并增强亲细胞亡信号传递.
结论:
- 已经确定了一种涉及CLN3,DNA损伤,c-Abl和YAP1在巴顿病病原体中的新型分子途径.
- 这种机制解释了CLN3的功能损失如何导致细胞功能障碍和亡.
- 针对c-Abl/YAP1轴为巴顿病提供了一个潜在的治疗策略.
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