素依赖的粉样蛋白形成驱动了溶酶体膜的机械破裂
bioRxiv : the preprint server for biology
|February 6, 2026
概括
L-leucyl-L-leucine甲基 (LLOMe) 在溶酶体内形成粉样结构,通过机械应力直接破裂膜. 这揭示了与神经退行和储存障碍相关的溶酶体损伤的新机制.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生物化学
- 神经科学是一个神经科学.
背景情况:
- 溶解体膜完整性对细胞健康至关重要,其破坏有助于溶解体储存障碍 (LSD) 和神经退行.
- L-leucyl-L-leucine甲基 (LLOMe) 是诱导和研究 lysosomal 损伤的常见工具,但其精确的作用机制尚不清楚.
研究的目的:
- 阐明LLOMe引起 lysosomal损伤的结构机制.
- 为了研究粉样蛋白形成在LLOMe诱导的溶酶体膜破裂中的作用.
主要方法:
- 低温电子断层扫描用于可视化LLOMe诱导的培养细胞和初级神经元的损伤.
- 为了确认观察到的机制,进行了体外复制实验.
主要成果:
- 在 lysosomal 光圈内,LLOMe 形成了粉样结构.
- 这些粉样结构通过机械应力直接与溶酶体膜相互作用并破裂.
- 这些发现通过体外溶解得到了验证.
结论:
- 由LLOMe诱导的溶酶体损伤是由粉样结构的形成介导的,这些结构会导致溶酶体膜的机械破裂.
- 这项研究建立了溶酶体膜破坏的结构性范式.
- 这些发现提供了关于与疾病相关的蛋白质聚合物如何在神经退行性疾病和LSD中损害 lysosomal 完整性的见解.
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