Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia

Abstract

The mechanistic target of rapamycin (also known as mammalian target of rapamycin) (mTOR)-dependent signaling pathway plays an important role in protein synthesis, cell growth, and proliferation, and has been linked to the development of the central nervous system. Recent studies suggest that mTOR signaling pathway dysfunction could be involved in the etiopathogenesis of schizophrenia. The main goal of this study was to evaluate the status of mTOR signaling pathway in postmortem prefrontal cortex (PFC) samples of subjects with schizophrenia. For this purpose, we quantified the protein expression and phosphorylation status of the mTOR downstream effector ribosomal protein S6 as well as other pathway interactors such as Akt and GSK3b. Furthermore, we quantified the status of these proteins in the brain cortex of rats chronically treated with the antipsychotics haloperidol, clozapine, or risperidone. We found a striking decrease in the expression of total S6 and in its active phosphorylated form phospho-S6 (Ser235/236) in the brain of subjects with schizophrenia compared to matched controls. The chronic treatment with the antipsychotics haloperidol and clozapine affected both the expression of GSK3b and the activation of Akt [phospho-Akt (Ser473)] in rat brain cortex, while no changes were observed in S6 and phospho-S6 (Ser235/236) protein expression with any antipsychotic treatment. These findings provide further evidence for the involvement of the mTOR-dependent signaling pathway in schizophrenia and suggest that a hypofunctional S6 may have a role in the etiopathogenesis of this disorder.

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

“…Increased mTORC1 activity and glycolysis was also seen in olanzapine [ 60 ], a second-generation antipsychotic, similar to what we found in cells treated with risperidone. In contrast to our results, Ibarra-Lecue et al have shown that only haloperidol, and not risperidone, increased the activation of the AKT/mTORC1 pathway [ 55 ]. However, a drug-regulated transcriptional study by Korostynski et al revealed that second-generation antipsychotics, including risperidone, strongly induced the transcription of mTOR pathway-related genes [ 61 ].…”

“…Cell proliferation is another function attributed to mTOR activity, while cells with strong mTOR inhibition have reduced viability [ 54 ]. Finally, mTORC1-dependent signaling has been linked in post-mortem animal studies with schizophrenia, specifically the hypofunction of the ribosomal protein S6 [ 55 ].…”

Cannabis Use Induces Distinctive Proteomic Alterations in Olfactory Neuroepithelial Cells of Schizophrenia Patients

“…In fact, metabolism of RNA was consistently deregulated in SCZ/c in every functional comparison. Although prior studies have found deregulations in ribosomal and RNA-related proteins in human samples from SCZ patients [53,54], our data revealed functional differences in metabolism of RNA exclusively linked to the coexistence of cannabis consumption and SCZ. According to REACTOME, MTREX and ZNF326 are involved in the same step of pre-mRNA processing prior to protein translation.…”

Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?

“…In addition, drugs of abuse and antipsychotics also regulate RPS6 phosphorylation [ 392 ]. Interestingly, the p-RPS6 level in schizophrenia is reduced [ 393 ]. Elevated expression or phosphorylation of RPS6 has also been found in multiple sclerosis [ 394 ].…”