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核细胞质HDAC抑制驱动了乙化依赖的TDP-43错位化和二硫化物相关的寡合化

Nataliia Lukianenko¹, Dong Min Kang², Aybuke Bekci¹

¹Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul 02792,Republic of Korea.

Journal of molecular biology

|July 3, 2025

概括

激素脱乙酶 (HDAC) 抑制在像ALS和FTLD这样的神经退行性疾病中触发TDP-43蛋白聚合. 针对特定的HDACs,特别是穿HDAC4/5,显示出对治疗TDP-43蛋白病变的希望.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
细胞生物学细胞生物学

背景情况:

包括ALS和FTLD在内的TDP-43蛋白病变,涉及异常的TDP-43聚合.
了解TDP-43聚合机制对于开发疗法至关重要.

研究的目的:

为了研究基因组脱乙酶 (HDACs) 在TDP-43寡合化中的作用.
为了确定调节TDP-43细胞质错位和聚合的特定HDACs.

主要方法:

建立了一个活细胞TDP43-BiFC模型,用于实时可视化TDP-43寡合化.
选了各种细胞压力因素,重点关注HDAC抑制剂 (LMK-235,MS-275,图巴斯丁A).
分析了TDP-43的乙化和二硫化键的形成.

主要成果:

抑制HDAC强烈触发了TDP-43的寡合化.
选择性抑制穿HDAC4/5与LMK-235强烈诱导的细胞质TDP-43寡合体.
核HDAC抑制 (MS-275) 在核中保留了TDP-43,而细胞质HDAC6抑制 (图巴斯A) 没有影响.
抑制HDAC增加了TDP-43的乙化和稳定,二硫化物结合的寡合物.

结论:

氨酸乙化是二硫化键依赖的TDP-43寡合化的关键调节剂.
针对核细胞质HDACs代表了TDP-43蛋白质病变的潜在治疗策略.

关键词:

在TDP-43的寡合化过程中.在TDP43-BiFC中使用.细胞质错位化错位化形成二硫化物键的形成.穿HDACs的运输时间

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