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Sandhoff disease (SD) is an LSD caused by a deficiency in the \u03b2 subunit of the \u03b2-hexosaminidase enzyme (<jats:italic>Hexb<\/jats:italic>). Although <jats:italic>Hexb<\/jats:italic> 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 \u03b2-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the <jats:italic>Hexb<\/jats:italic>\n            <jats:sup>-\/-<\/jats:sup> SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces <jats:italic>Hexb<\/jats:italic>\n            <jats:sup>-\/-<\/jats:sup> microglia with <jats:italic>Hexb<\/jats:italic>-sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores \u03b2-hexosaminidase enzymatic activity and <jats:italic>Hexb<\/jats:italic> expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived \u03b2-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy.<\/jats:p>","DOI":"10.1038\/s41467-025-63237-0","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T08:19:21Z","timestamp":1756282761000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived \u03b2-hexosaminidase is necessary for neuronal health"],"prefix":"10.1038","volume":"16","author":[{"given":"Kate I.","family":"Tsourmas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9320-8297","authenticated-orcid":false,"given":"Claire A.","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8890-4976","authenticated-orcid":false,"given":"Nellie E.","family":"Kwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary R.","family":"Sloane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koby J. 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