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GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles

Published:25 March 2025 DOI: 10.1016/j.celrep.2025.115343 PMID: 39992792
Mei Liu,?Jianping Zhu,?Jiawei Zheng,?Xuan Han,?Lijuan Jiang,?Xiangzhen Tong,?Yue Ke,?Zhipeng Guo,?Weiyuan Huang,?Jin Cong,?Meiqiu Liu,?Su-Yan Lin,?Shuang Zhu,?Li Mei,?Xingmei Zhang,?Wangming Zhang,?Wen-Jun Xin,?Zhenhai Zhang,?Yanwu Guo,?Rongqing Chen

Abstract

Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 238 suppliers $23.00-$2200.00
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 238 suppliers $23.00-$2200.00
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 238 suppliers $23.00-$2200.00
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 238 suppliers $23.00-$2200.00
EN6 1808714-73-9 C19H14F2N4O2 45 suppliers $29.00-$2986.90
EN6 1808714-73-9 C19H14F2N4O2 45 suppliers $29.00-$2986.90
EN6 1808714-73-9 C19H14F2N4O2 45 suppliers $29.00-$2986.90
EN6 1808714-73-9 C19H14F2N4O2 45 suppliers $29.00-$2986.90

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