Reactivation of mTOR signaling slows neurodegeneration in a lysosomal storage disease

Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of GM2 ganglioside and GA2 glycolipid. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function–related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases Compare gene expression level from WT, HexbKO, KOTsc, Tsc brain with six replicates from each group.

桑德霍夫病（Sandhoff disease）是一种溶酶体贮积症（lysosomal storage disorder），由HEXB基因的致病变异引发，导致β-己糖胺酶（β-hexosaminidase）活性丧失以及GM2神经节苷脂（GM2 ganglioside）与GA2糖脂（GA2 glycolipid）的异常蓄积。该蓄积主要发生于神经元内，并通过目前尚不明确的分子机制引发进行性神经退行性变。溶酶体贮积症常伴随mTOR信号通路（mTOR signaling）功能异常，该通路对神经元的正常发育与生理功能至关重要。本研究中，桑德霍夫病模型小鼠脑内的mTOR信号通路活性显著降低。为验证恢复mTOR信号通路是否可改善疾病表型，我们通过遗传学手段在该模型小鼠中降低了mTOR抑制剂Tsc2的表达水平。恢复mTOR信号通路活性的桑德霍夫病模型小鼠展现出更高的存活率与更优的运动功能，其中雌性小鼠的改善效果尤为显著；同时其树突棘密度升高，神经退行性变程度得以减轻。降低Tsc2表达还部分挽救了异常的突触功能相关基因表达谱。上述研究结果提示，增强mTOR信号通路或许可成为治疗溶酶体相关神经退行性疾病的潜在治疗策略。请对野生型（WT）、Hexb基因敲除型（HexbKO）、KOTsc型以及单纯Tsc敲除型（Tsc）的脑组织样本进行基因表达水平比较，每组设置6个生物学重复。