Extended Data Fig. 10: Graphical abstract of experimental findings.
From: Microglia–neuron crosstalk through Hex–GM2–MGL2 maintains brain homeostasis
Left panel (Homeostasis): In the healthy brain, microglia expressing high levels of Hexb secrete functional Hex, which is taken up by neurons and delivered to their lysosomes. Middle panel (Sandhoff disease/model): In the absence of Hexb, both microglia and neurons accumulate GM2 ganglioside in their lysosomes. Neuronal cell death leads to extracellular GM2 release, which is sensed by microglia via the receptor MGL2, recognizing terminal GalNAc residues. This triggers a pro-inflammatory response, including the upregulation and secretion of TNF, IL-6, CCL3, CCL4, and CCL17. Right panel (Microglia replacement therapy): Transplantation of wild-type microglia into Hexb-deficient brains restores enzymatic function in neurons via microglial enzyme supply. The replaced microglia secrete functional Hex, thereby reducing neuronal and CNS-wide GM2 accumulation and promoting restoration of CNS homeostasis. Illustrations created using BioRender (https://biorender.com).
