Reduced protein synthesis in schizophrenia patient-derived olfactory cells.

J A English,N Matigian,P Dicker,M Föcking,G Cagney,Y Fan,K Wynne,A Mackay-Sim,D R Cotter,L M Lopez,M Hryniewiecka

doi:10.1038/tp.2015.119

Abstract

Human olfactory neurosphere-derived (ONS) cells have the potential to provide novel insights into the cellular pathology of schizophrenia. We used discovery-based proteomics and targeted functional analyses to reveal reductions in 17 ribosomal proteins, with an 18% decrease in the total ribosomal signal intensity in schizophrenia-patient-derived ONS cells. We quantified the rates of global protein synthesis in vitro and found a significant reduction in the rate of protein synthesis in schizophrenia patient-derived ONS cells compared with control-derived cells. Protein synthesis rates in fibroblast cell lines from the same patients did not differ, suggesting cell type-specific effects. Pathway analysis of dysregulated proteomic and transcriptomic data sets from these ONS cells converged to highlight perturbation of the eIF2α, eIF4 and mammalian target of rapamycin (mTOR) translational control pathways, and these pathways were also implicated in an independent induced pluripotent stem cell-derived neural stem model, and cohort, of schizophrenia patients. Analysis in schizophrenia genome-wide association data from the Psychiatric Genetics Consortium specifically implicated eIF2α regulatory kinase EIF2AK2, and confirmed the importance of the eIF2α, eIF4 and mTOR translational control pathways at the level of the genome. Thus, we integrated data from proteomic, transcriptomic, and functional assays from schizophrenia patient-derived ONS cells with genomics data to implicate dysregulated protein synthesis for the first time in schizophrenia.

Highlights

Schizophrenia is among the most disabling of human diseases, with poorly understood pathophysiology.[1]
Schizophrenia patient-derived fibroblasts were larger than control-derived fibroblast cells (2650 +95 versus 2151+29 μm[2]; F1,336 = 27.33; Po 0.0001). These findings demonstrate that the reduced expression of ribosomal proteins in schizophrenia patient-derived olfactory neurosphere-derived (ONS) cells was associated with a significant reduction in the rate of protein synthesis compared with ONS cells from healthy controls
We quantified global protein synthesis rates and demonstrated that patient-derived cell lines had significantly reduced rates of protein synthesis compared with control-derived cell lines

Summary

Introduction

Schizophrenia is among the most disabling of human diseases, with poorly understood pathophysiology.[1]. We reasoned that protein expression changes in olfactory neurosphere-derived (ONS) cells may provide novel insights into cellular processes that are dysregulated in schizophrenia. Patient-derived neural cell models of schizophrenia such as those derived from nasal biopsy of the olfactory mucosa, used here, do not require genetic reprogramming and can be obtained from adults with complex genetic disorders.[2,3] Research in schizophrenia patient-derived olfactory cells has already revealed insights into specific microRNA effects that are in keeping with the molecular changes associated with schizophrenia,[4,5,6] as well as disease-associated alterations of cell cycle, cellular adhesion and migration.[7,8] Disease-associated alterations in migration, along with dysregulated cytoskeletal genes and proteins, were observed in neural progenitor cells generated from schizophreniaderived induced pluripotent stem cells (iPSCs).[9] Our objective was to identify disease-associated cellular processes in schizophrenia patient-derived ONS cells. Our strategy was to use discoverybased protein expression profiling to identify significantly altered processes and pathways and examine those altered pathways at a functional level

Objectives

Methods

Findings

Conclusion