Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage.

© 2025. The Author(s).

基于遗传学研究，溶酶体功能障碍被认为在帕金森病的发病机制中起着重要作用。在这里，我们展示了VPS13C（一种脂质转运蛋白和一个与帕金森病相关的基因）是溶酶体应激或损伤的感受器。在溶酶体膜受到干扰后，VPS13C会迅速从细胞质重新定位到溶酶体表面，并将其膜固定到内质网上。这种再定位依赖于Rab7，并且需要一个信号释放受损的溶酶体表面上的抑制状态，这阻碍了其VAB域与结合在溶酶体上的Rab7的接触。虽然另一种帕金森病蛋白LRRK2也会被招募到应激或损伤的溶酶体中，但它的再定位发生在较晚阶段，并且通过不同的机制进行。鉴于VPS13蛋白在大量脂质转运中的作用，这些发现表明由VPS13C向溶酶体递送脂质是应对溶酶体损伤的一种早期保护性反应的一部分。

© 2025. The Author(s).