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<p>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 (<i>Hexb</i>). Although <i>Hexb</i> 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 <i>Hexb</i><sup>-/-</sup> SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces <i>Hexb</i><sup>-/-</sup> microglia with <i>Hexb</i>-sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and <i>Hexb</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月27日

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  • 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

摘要

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.