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bioRxiv · 10.1101/2024.06.24.600387

Human induced pluripotent stem cell-derived microglia contribute to thepathophysiology of Fragile X syndrome via increased RAC1 signaling

banerjee, p.·Sharma, S. D.·Burr, K.·Morris, K.·Ritakari, T.·Baxter, P.·Cooper, J. D.·Cardinalli, A.·Subash, S.·Paza, E.·Story, D.·Chattarji, S.·Kind, P. C.·Carragher, N.·Selvaraj, B. T.·Priller, J.·Chandran, S.
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Abstract

Fragile X syndrome (FXS) is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism and epilepsy. Emerging evidence suggests a role for immune dysfunction in autism. Using induced pluripotent stem cell (iPSC)-derived microglial cells from FXS patients (mFXS-MG) and FMR1-deficient microglia from FMR1-knock out human embryonic stem cells (FMR1 KO-MG), we show that loss-of-function of Fragile X Messenger Ribonucleoprotein (FMRP) leads to cell autonomous phagocytic deficits and a proinflammatory state in microglia when compared to gene-corrected controls. Moreover, increased RAC1 signaling in mFXS-MG and FMR1 KO-MG results in increased actin polymerization and enhanced activation of NF-{kappa}B signaling. Exposure of control iPSC-derived cortical neuron cultures to conditioned medium from proinflammatory mFXS-MG results in hyperexcitability. Importantly, pharmacological inhibition of RAC1 signaling in mFXS-MG attenuates their proinflammatory profile and corrects the neuronal hyperexcitability caused by the conditioned medium. Our results suggest that microglia impair neuronal function in FXS, which can be prevented by targeting of RAC1 signaling. Significance statementFXS is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy and has been associated with immune dysfunction. We therefore generated brain macrophages (microglia) from patient-derived induced pluripotent stem cells (mFXS-MG) and an embryonic stem cell line deficient in the Fragile X messenger ribonucleoprotein 1 (FMR1 KO-MG). We find enhanced activation of RAC1 signaling resulting in phagocytic deficits and immune activation of mFXS-MG and FMR1 KO-MG. Exposure of control iPSC-derived cortical neurons to conditioned medium from proinflammatory mFXS-MG results in neuronal hyperexcitability, which can be prevented by pharmacological RAC1 inhibition in mFXS-MG. We conclude that RAC1 signaling in microglia could be a potential therapeutic target in FXS.

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banerjee, p., Sharma, S. D., Burr, K., Morris, K., Ritakari, T., Baxter, P., Cooper, J. D., Cardinalli, A., Subash, S., Paza, E., Story, D., Chattarji, S., Kind, P. C., Carragher, N., Selvaraj, B. T., Priller, J., Chandran, S.. 2024-06-28. Human induced pluripotent stem cell-derived microglia contribute to thepathophysiology of Fragile X syndrome via increased RAC1 signaling. https://doi.org/10.1101/2024.06.24.600387

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