Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS–STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann–Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.

溶酶体贮积症 (LSD) 的特点是遗传和代谢溶酶体功能障碍，构成 60 多种退行性疾病，带来相当大的健康和经济负担。然而，由于溶酶体缺陷导致功能细胞逐渐死亡的机制仍未完全了解，并且缺乏针对 LSD 的广谱治疗方法。在这里，我们发现导致 LSD 的各种基因异常，包括Hexb、Gla、Npc1、Ctsd和Gba，都具有共同的特性，可以强有力地自动激活神经元固有的 cGAS-STING 信号传导，从而驱动神经元死亡和疾病进展。这种信号传导是由神经元中 dsDNA 和 DNA 传感器 cGAS 的过量细胞质聚集触发的。cGAS 或 STING 的基因消融、DNase 对神经元胞质 dsDNA 的消化以及神经元溶酶体功能障碍的修复减轻了桑德霍夫病、法布里病和尼曼-匹克病的症状，并显着减少了神经元损失。因此，我们确定了介导各种LSD发病机制的普遍机制，揭示了溶酶体缺陷与先天免疫之间的内在联系，并提出了治疗LSD的统一策略。