Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health

  • Nat Commun. 2025 Aug 27;16(1):7994. doi: 10.1038/s41467-025-63237-0.
Kate I Tsourmas  1  2 ,  Claire A Butler  1  2 ,  Nellie E Kwang  1  2 ,  Zachary R Sloane  1  2 ,  Koby J G Dykman  1  2 ,  Ghassan O Maloof  1  2 ,  Biswa P Choudhury  3 ,  Mousumi Paulchakrabarti  3 ,  Christiana A Prekopa  1  2 ,  Emily Z Tabaie  1  2 ,  Robert P Krattli  4 ,  Sanad M El-Khatib  4 ,  Vivek Swarup  1  2 ,  Munjal M Acharya  4  5 ,  Lindsay A Hohsfield  1  2 ,  Kim N Green  6  7
Affiliations
  • 1. Department of Neurobiology and Behavior; University of California, Irvine, CA, USA.
  • 2. Institute for Memory Impairments and Neurological Disorders; University of California, Irvine, CA, USA.
  • 3. GlycoAnalytics Core, Glycobiology Research and Training Center, School of Medicine, University of California, San Diego, CA, USA.
  • 4. Department of Anatomy and Neurobiology; University of California, Irvine, CA, USA.
  • 5. Department of Radiation Oncology; University of California, Irvine, CA, USA.
  • 6. Department of Neurobiology and Behavior; University of California, Irvine, CA, USA. [email protected].
  • 7. Institute for Memory Impairments and Neurological Disorders; University of California, Irvine, CA, USA. [email protected].
PMID: 40866328 DOI: 10.1038/s41467-025-63237-0
Abstract

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.

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