Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health
- Kate I. Tsourmas
- Claire A. Butler
- Nellie E. Kwang
- Zachary R. Sloane
- Koby J. G. Dykman
- Ghassan O. Maloof
- Biswa P. Choudhury
- Mousumi Paulchakrabarti
- Christiana A. Prekopa
- Emily Z. Tabaie
- Robert P. Krattli
- Sanad M. El-Khatib
- Vivek Swarup
- Munjal M. Acharya
- Lindsay A. Hohsfield
- Kim N. Green
2025-08-27
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 ( Hexb ). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To investigate how a microglial gene is involved in neuronal homeostasis, here we show that β-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the Hexb -/- SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces Hexb -/- microglia with Hexb -sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and Hexb expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived β-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy.