GPR34 regulation of disease-associated microglial states and responses to physiological stimuli

Geller, A.; Kwon, M. J.; Simmons, S. K.; Xu, Q.; Martenis, W. E.; Doman, J.; Natarajan, S.; Stalnaker, K. J.; Zhang, J.; Adiconis, X.; Nguyen, T.; Demers, M.; Batzli, D.; Valle-Tojeiro, A.; Biji, C.; Aryal, S.; Pribiag, H.; Depp, C.; Morshed, N.; Misri, D.; Bohannon, D.; Longhi, E.; Keshishian, H.; Carr, S. A.; McKinney, D.; Gould, A. E.; Lebois, E.; Weiwer, M.; Johnson, M.; Levin, J. Z.; Zhang, Y.-L.; Sheng, M.; Kunwar, P. S.

doi:10.1101/2025.11.26.690816

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bioRxiv · 10.1101/2025.11.26.690816

GPR34 regulation of disease-associated microglial states and responses to physiological stimuli

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Abstract

Expression of the G protein coupled receptor GPR34 is highly enriched in microglia and has been reported to be downregulated in several brain disease contexts, including Alzheimers disease (AD) and multiple sclerosis (MS). GPR34 function is poorly understood, as is its role in regulation of microglial states. Using RNA-sequencing, we find that microglia from Gpr34 knockout (KO) mouse brains exhibited a transcriptomic shift toward disease-associated microglia (DAM) and inflammatory profiles, partially resembling the microglial phenotype seen in 5xFAD AD model mice. Moreover, when Gpr34 KO mice were crossed with 5xFAD mice, the DAM transcriptional profile of microglia and glial pathology were further enhanced beyond the already robust DAM signature driven by 5xFAD alone. This occurred without affecting amyloid plaque burden. Human stem cell-derived microglia (iMGLs) lacking GPR34 showed reduced calcium (Ca{superscript 2}) and phosphorylated ERK (pERK) signaling in response to stimulation with known GPR34 agonists (lyso-phosphatidylserine (lysoPS) and myelin), as well as transcriptomic changes in immune regulation and cell proliferation related pathways. Interestingly, GPR34 KO iMGLs were selectively impaired in phagocytosis of myelin but not amyloid-{beta} (A{beta}) or E. coli, and showed a diminished transcriptional response elicited by myelin. Together, these findings suggest that GPR34 is important for maintaining microglia in a homeostatic state, promotes phagocytosis of and transcriptional response to myelin, and limits microglial activation in neurodegenerative disease conditions.

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Geller, A., Kwon, M. J., Simmons, S. K., Xu, Q., Martenis, W. E., Doman, J., Natarajan, S., Stalnaker, K. J., Zhang, J., Adiconis, X., Nguyen, T., Demers, M., Batzli, D., Valle-Tojeiro, A., Biji, C., Aryal, S., Pribiag, H., Depp, C., Morshed, N., Misri, D., Bohannon, D., Longhi, E., Keshishian, H., Carr, S. A., McKinney, D., Gould, A. E., Lebois, E., Weiwer, M., Johnson, M., Levin, J. Z., Zhang, Y.-L., Sheng, M., Kunwar, P. S.. 2025-12-01. GPR34 regulation of disease-associated microglial states and responses to physiological stimuli. https://doi.org/10.1101/2025.11.26.690816

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