Elsevier

Neuroscience Research

Volume 175, February 2022, Pages 73-81
Neuroscience Research

Dysregulation of DPYSL2 expression by mTOR signaling in schizophrenia: Multi-level study of postmortem brain

https://doi.org/10.1016/j.neures.2021.09.004Get rights and content
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open access

Highlights

  • DPYSL2 and mTOR-signaling cascade in schizophrenia brain were studied.

  • mTOR expression was increased in the PFC.

  • S6 expression was decreased in the PFC and STG.

  • Dysregulation of DPYSL2 expression by mTOR signaling was suggested.

Abstract

The mechanistic target of rapamycin (mTOR)-signaling and dihydropyrimidinase-like 2 (DPYSL2), which are increasingly gaining attention as potential therapeutic targets for schizophrenia, are connected via Cap-dependent translation of the 5′TOP motif. We quantified the expression of molecules constituting the mTOR-signaling and DPYSL2 in the prefrontal cortex (PFC) and superior temporal gyrus (STG) of postmortem brain tissue samples from 24 patients with schizophrenia and 32 control individuals and conducted association analysis to examine abnormal regulation of DPYSL2 expression by the mTOR-signaling in schizophrenia. The average ribosomal protein S6 (S6) levels in the PFC and STG were lower in patients with schizophrenia (p < 0.01). DPYSL2 expression showed a significant positive correlation with phospho-S6 expression levels, which were effectors of mTOR translational regulation, and the correlation slope between phospho-S6 and DPYSL2 expressions differed between cases and controls. Association analyses of these mTOR-signaling and DPYSL2 alterations with genetic polymorphisms and the clinical profile suggested that certain genetic variants of DPYSL2 require high mTOR-signaling activity. Thus, the findings confirmed decreased S6 expression levels in schizophrenia and supported the relationship between the mTOR-signaling and DPYSL2 via 5′TOP Cap-dependent translation, thus providing insights connecting the two major schizophrenia treatment strategies associated with the mTOR-signaling and DPYSL2.

Abbreviations

ANCOVA
analysis of covariance
BSA
bovine serum albumin
DIBS
diagnostic instrument for brain studies
DLPFC
dorsolateral prefrontal cortex
DNR
dinucleotide repeat
DOI
duration of illness
ELISA
enzyme-linked immunosorbent assay
GWAS
genome-wide association study
mTOR
mechanistic target of rapamycin
PFC
prefrontal cortex
PMI
postmortem interval
SNP
single-nucleotide polymorphism
STG
superior temporal gyrus
UTR
untranslated region

Keywords

Schizophrenia
Postmortem-brain
mTOR
RPS6
DPYSL2

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