浙江大学徐平龙等研究人员合作发现，溶酶体功能障碍的先天免疫感应驱动多种溶酶体贮积症。该项研究成果于2024年1月22日在线发表在《自然—细胞生物学》杂志上。

研究人员发现了导致溶酶体贮积症（LSD）的各种基因异常，包括Hexb、Gla、Npc1、Ctsd和Gba，都具有共同的特性，即能强有力地自动激活神经元内在的cGAS-STING信号，驱动神经元死亡和疾病进展。这种信号是由神经元中dsDNA和DNA传感器cGAS在细胞质中的过度聚集引发的。基因敲减cGAS或STING、用DNase消化神经元胞浆dsDNA以及修复神经元溶酶体功能障碍可减轻Sandhoff病、法布里病和Niemann-Pick病的症状，同时大幅减少神经元的损失。

因此，研究人员发现了一种介导多种LSD发病机制的普遍机制，揭示了溶酶体缺陷与先天性免疫之间的内在联系，并提出了治疗LSD的统一策略。

据悉，LSD以遗传和代谢性溶酶体功能障碍为特征，是60多种退行性疾病之一，对健康和经济造成相当大的负担。然而，人们对溶酶体缺陷导致功能细胞逐渐死亡的机制仍不完全清楚，也缺乏针对LSD的广谱疗法。

附：英文原文

Title: Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders

Author: Wang, Ailian, Chen, Chen, Mei, Chen, Liu, Shengduo, Xiang, Cong, Fang, Wen, Zhang, Fei, Xu, Yifan, Chen, Shasha, Zhang, Qi, Bai, Xueli, Lin, Aifu, Neculai, Dante, Xia, Bing, Ye, Cunqi, Zou, Jian, Liang, Tingbo, Feng, Xin-Hua, Li, Xinran, Shen, Chengyong, Xu, Pinglong

Issue&Volume: 2024-01-22

Abstract: 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.

DOI: 10.1038/s41556-023-01339-x

Source: https://www.nature.com/articles/s41556-023-01339-x