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 and Kim N. Green ()
Additional contact information
Kate I. Tsourmas: Department of Neurobiology and Behavior; University of California
Claire A. Butler: Department of Neurobiology and Behavior; University of California
Nellie E. Kwang: Department of Neurobiology and Behavior; University of California
Zachary R. Sloane: Department of Neurobiology and Behavior; University of California
Koby J. G. Dykman: Department of Neurobiology and Behavior; University of California
Ghassan O. Maloof: Department of Neurobiology and Behavior; University of California
Biswa P. Choudhury: University of California
Mousumi Paulchakrabarti: University of California
Christiana A. Prekopa: Department of Neurobiology and Behavior; University of California
Emily Z. Tabaie: Department of Neurobiology and Behavior; University of California
Robert P. Krattli: Department of Anatomy and Neurobiology; University of California
Sanad M. El-Khatib: Department of Anatomy and Neurobiology; University of California
Vivek Swarup: Department of Neurobiology and Behavior; University of California
Munjal M. Acharya: Department of Anatomy and Neurobiology; University of California
Lindsay A. Hohsfield: Department of Neurobiology and Behavior; University of California
Kim N. Green: Department of Neurobiology and Behavior; University of California

Nature Communications, 2025, vol. 16, issue 1, 1-28

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63237-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63237-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63237-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().