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乌比基蛋白酶体系统组件,RAD23A和USP13,调节TDP-43溶解度和神经毒性
Casey Dalton1, Jelena Mojsilovic-Petrovic1, Nathaniel Safren1
1Department of Neurology, Northwestern University School of Medicine, Chicago, IL, United States.
概括
准RAD23A和USP13修饰基因为肌缩侧面硬化症 (ALS) 提供了一个新的治疗策略. 减少这些蛋白质可以提高TDP-43的溶解性,并降低ALS模型中的神经毒性.
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
- 遗传学 是一个遗传学.
背景情况:
- 肌缩侧面硬化 (ALS) 是一种致命的神经退行性疾病,其特征是TAR DNA结合蛋白 43 (TDP-43) 的错位和聚合.
- 细胞质中的TDP-43聚合是关键的病理特征,推动疾病的进展.
- 直接降低TDP-43不是一种可行的治疗方法,因为它具有重要的细胞功能.
研究的目的:
- 识别和描述修改TDP-43错位化和聚合的基因.
- 探索针对ALS中这些修饰基因的治疗潜力.
主要方法:
- 使用诱导性突变TDP-43 HEK293细胞系和初级大鼠神经元.
- 使用了RAD23A和USP13基因的淘汰.
- 应用基于发现的蛋白质组学来分析蛋白质组重塑.
- 在细胞和C. elegans模型中评估TDP-43的溶解性,聚合性和细胞毒性.
主要成果:
- 在细胞和神经元模型中,RAD23A的抑制降低了不溶性TDP-43水平.
- 蛋白质组分析发现USP13 (一种二维基因酶) 是TDP-43聚合的修饰剂.
- 击败USP13降低了TDP-43聚合,减少了运动神经元中的细胞死亡,并改善了C. elegans的运动功能.
结论:
- RAD23A和USP13,是ubiquitin蛋白酶体系统的组成部分,是TDP-43病理学的显著修饰剂.
- 向RAD23A和USP13可以提高TDP-43的溶解性,并减少TDP-43引起的神经毒性.
- 这些发现表明,准RAD23A和USP13等修饰基因代表了对ALS的有希望的治疗途径.
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