Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain

Hopp, S. C.; Garcia Rogers, J.; Smith, S.; Campos, G.; Miller, H.; Barannikov, S.; Gutierrez Kuri, E.; Wang, H.; Han, X.; Bieniek, K. F.; Weintraub, S. T.; Palavicini, J. P.

doi:10.1101/2023.12.06.570499

bioRxiv · 10.1101/2023.12.06.570499

Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain

Hopp, S. C.·Garcia Rogers, J.·Smith, S.·Campos, G.·Miller, H.·Barannikov, S.·Gutierrez Kuri, E.·Wang, H.·Han, X.·Bieniek, K. F.·Weintraub, S. T.·Palavicini, J. P.

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Abstract

Phospholipase C gamma-2 (PLC{gamma}2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), which subsequently feed into numerous downstream signaling pathways. PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimers disease (AD) and with longevity. In the brain, PLCG2 is highly expressed in microglia, where it is proposed to regulate phagocytosis, secretion of cytokines/chemokines, cell survival and proliferation. We analyzed the brains of three-month-old PLC{gamma}2 knockout (KO), heterozygous (HET), and wild-type (WT) mice using multiomics approaches, including shotgun lipidomics, proteomics, and gene expression profiling, and immunofluorescence. Lipidomic analyses revealed sex-specific losses of total cerebrum PIP2 and decreasing trends of DAG content in KOs. In addition, PLC{gamma}2 depletion led to significant losses of myelin-specific lipids and decreasing trends of myelin-enriched lipids. Consistent with our lipidomics results, RNA profiling revealed sex-specific changes in the expression levels of several myelin-related genes. Further, consistent with the available literature, gene expression profiling revealed subtle changes on microglia phenotype in mature adult KOs under baseline conditions, suggestive of reduced microglia reactivity. Immunohistochemistry confirmed subtle differences in density of microglia and oligodendrocytes in KOs. Exploratory proteomic pathway analyses revealed changes in KO and HET females compared to WTs, with over-abundant proteins pointing to mTOR signaling, and under-abundant proteins to oligodendrocytes. Overall, our data indicate that loss of PLC{gamma}2 has subtle effects on brain homeostasis that may underlie enhanced vulnerability to AD pathology and aging via novel mechanisms in addition to regulation of microglia function. Significance StatementThe PLCG2 gene contains a number of rare variants linked with increased and decreased risk for Alzheimers disease and longevity, but little is known about the role of PLC{gamma}2 in normal brain function. The results described herein are significant because they describe the effects of knockout of PLC{gamma}2 on brain cell types, thus mimicking the loss of function Alzheimers disease risk mutation. Our data describe novel effects of PLC{gamma}2 deficiency on myelin homeostasis and mTOR signaling that have not been previously described that may underlie its association with Alzheimers disease pathogenesis and longevity.

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Hopp, S. C., Garcia Rogers, J., Smith, S., Campos, G., Miller, H., Barannikov, S., Gutierrez Kuri, E., Wang, H., Han, X., Bieniek, K. F., Weintraub, S. T., Palavicini, J. P.. 2023-12-08. Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain. https://doi.org/10.1101/2023.12.06.570499

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