Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease.

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (). Although expression in the brain is specific to microglia, SD primarily affects neurons. To understand how a microglial gene is involved in maintaining neuronal homeostasis, we demonstrated that β-hexosaminidase is secreted by microglia and integrated into the neuronal lysosomal compartment. To assess therapeutic relevance, we treated SD mice with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaced microglia with -sufficient cells. This intervention reversed apoptotic gene signatures, improved behavior, restored enzymatic activity and expression, ameliorated substrate accumulation, and normalized neuronal lysosomal phenotypes. These results underscore the critical role of myeloid-derived β-hexosaminidase in neuronal lysosomal function and establish microglial replacement as a potential LSD therapy.