Phosphoproteomics identifies Rho-Kinase-associated phospho-signaling in the medial prefrontal cortex of a schizophrenia-related mouse model and discloses autophagy dysfunction
W. Zhu1, R. Tanaka1, T. Nakai1,2, T. Nagai3,4, T. Nabeshima5,6, K. Kaibuchi4,7, N. Ozaki8, H. Ikesue1, H. Mizoguchi1, K. Yamada1,3
1Nagoya University Graduate School of Medicine, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya, Japan, 2Fujita Health University School of Medicine, Department of Pharmacotherapeutics and Informatics, Toyoake, Japan, 3Fujita Health University School of Medicine, Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Toyoake, Japan, 4Fujita Health University, Fujita Mind-Brain Research & Innovation Center for Drug Generation (Fujita Mind-BRIDGe), Toyoake, Japan, 5Fujita Health University Graduate School of Medical Sciences, Laboratory of Health and Medical Science Innovation, Toyoake, Japan, 6Fujita Health University, ICBS, Toyoake, Japan, 7Fujita Health University, Division of Cell Biology, ICBS, Toyoake, Japan, 8Nagoya University Graduate School of Medicine, Pathophysiology of Mental Disorders, Nagoya, Japan
Background: Schizophrenia is a chronic, debilitating psychiatric disorder with high heritability. We have previously established a schizophrenia-associated mouse model, Arhgap10 S490P/NHEJ (Arhgap10) mice, which carries a missense variant (p.S490P) together with a frameshift mutation arising from non-homologous end-joining (NHEJ), both identified in a Japanese schizophrenia patient. These mice exhibited activated Rho-kinase (ROCK) signaling cascade, schizophrenia-related behavioral and neurobiological phenotypes that were ameliorated by the ROCK inhibitor fasudil.
Aims & Objectives: Although phospho-signaling is increasingly implicated in schizophrenia pathophysiology, comprehensive phosphoproteomic profiling in the brain of Arhgap10 mice has not yet been performed, leaving key downstream ROCK-dependent targets unidentified.
Method: Here, we conducted unbiased phosphoproteomic analysis of the medial prefrontal cortex (mPFC) of wild-type (WT) and Arhgap10 mice, treated with or without fasudil.
Results: We identified 15 phosphoproteins that were significantly upregulated in the mPFC of Arhgap10 mice compared with WT controls. Among these, phosphorylated microtubule-associated protein tau at serine 404 (pTau_S404), phosphorylated autophagy-related protein 9A at serine 828 (pATG9A_S828), and phosphorylated serine/threonine-protein kinase WNK2 at threonine 282 (pWNK2_T282) were markedly reduced to control levels by fasudil treatment. Since these candidates are functionally linked to autophagy regulation, we further examined autophagy status. An impaired autophagy activity was observed in the mPFC of Arhgap10 mice.
Discussion & Conclusions: This study provides the first phosphoproteomic network map of the mPFC in the Arhgap10 mouse model of schizophrenia, demonstrating increased ROCK-dependent phosphoproteins and autophagy dysfunction.
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