溶酶体和mTORC1信号失调是80型性的病理基础
Yiqiang Zhi1,2, Tongtong Zhang1,2, Danping Lu3
1Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
Nature communications
|November 7, 2025
概括
在遗传性性 (HSP) 中,UBAP1蛋白对溶酶体修复至关重要. 在小鼠模型中,用拉巴胺素恢复其功能改善了 lysosome 的健康,并减缓了疾病的进展.
科学领域:
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
背景情况:
- 运输所需的内分体分类复合体 (ESCRT) 机器对于膜重塑,内分体修复至关重要,并且与遗传性性 (HSP) 有关.
- 作为ESCRT-I组件的UBAP1中的功能丧失突变会导致性80 (SPG80),这是一种罕见的HSP形式,但病理机制仍然难以捉摸.
研究的目的:
- 阐明UBAP1在溶酶体修复中的作用及其与HSP病变发生的联系.
- 研究将UBAP1缺乏与细胞功能障碍联系起来的分子机制.
- 评估针对UBAP1相关疾病中mTORC1信号的治疗潜力.
主要方法:
- 使用体外和体外模型研究了UBAP1对受损溶酶体的招募及其在溶酶体恢复中的作用.
- 评估了UBAP1损失对溶酶体功能,mTOR局部化和TFEB酸化的影响.
- 给Ubap1缺乏的小鼠服用mTORC1抑制剂Rapamycin,以评估其治疗效果.
主要成果:
- UBAP1,但不是SPG80引起的突变,有效地局部化到受损的溶酶体并调解其修复.
- 丢失UBAP1破坏了溶酶体功能,导致脱离的mTOR定位,细胞质mTORC1激活和TFEB脱.
- 拉巴胺治疗恢复了溶酶体mTOR局部化和TFEB酸化,减轻了疾病进展,并在Ubap1缺乏的小鼠中恢复了溶酶体平衡.
结论:
- UBAP1在维持 lysosomal 恒温和修复方面发挥着至关重要的作用.
- 功能障碍的UBAP1会破坏mTORC1-TFEB通路,从而导致HSP的发病.
- 针对mTORC1与拉巴素显示承诺作为SPG80和潜在的其他运动神经元疾病的治疗策略.
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