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mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain

Abstract

The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.

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Fig. 1: Abnormal phosphorylation of downstream effector proteins of mTOR complexes in SZ DLPFC.
Fig. 2: Chronic antipsychotic treatment leads to increased phosphorylation of S6RP in rat brain.
Fig. 3: Rapamycin differentially inhibits the activity of mTOR and related kinases in SZ DLPFC.

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Acknowledgements

The authors would like to thank Dr. Rosalinda Roberts and the Alabama Brain Collection for postmortem cortical samples used in assay development for immunoblotting analyses.

Funding

RC was supported by the Marie and Emmett Carmichael fund for graduate students in biosciences. KA and REM were supported by NIMH R01 MH107487 and MH121102.

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Authors RC and JMW designed the study. RC executed experimental protocols, performed data calculations, statistical analyses, and literature searches. RC performed the biochemical studies, whereas kinome array experiments were executed and analyzed by KA. RC wrote the first draft of the manuscript, followed by editing by JMW and REM. All authors contributed to and have approved the final manuscript.

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Correspondence to Radhika Chadha.

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Chadha, R., Alganem, K., Mccullumsmith, R.E. et al. mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01135-9

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