2. Academic Validation
  3. Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health

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

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. kngreen@uci.edu.
  • 7 Institute for Memory Impairments and Neurological Disorders; University of California, Irvine, CA, USA. kngreen@uci.edu.
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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