Adolescent-onset and adult-onset schizophrenia: reduced ribosomal protein expression via mTOR signalling in patient-derived olfactory cells

Abstract

Schizophrenia is a heterogeneous disorder associated with many genetic and environmental risk factors that could affect brain development. It is unknown whether adolescent-onset and adult-onset schizophrenia have similar aetiology. To address this we used discovery-based proteomics to find proteins differentially expressed in olfactory neurosphere-derived cells from adolescents with schizophrenia compared to age- and gender-matched healthy controls. Of 1638 proteins identified, 241 were differentially expressed in patient cells, with significant down-regulation of ribosomal and cytoskeletal proteins, and dysregulation of protein synthesis pathways. We then re-analysed our previous adult-onset proteomic data to compare directly with adolescent-onset protein expression. Schizophrenia-associated protein expression in adult-onset patients was remarkably similar to adolescent-onset patients. To increase sample size and power we combined the two datasets for a bioinformatic meta-analysis. Schizophrenia-associated protein expression indicated significant downregulation of the mTOR signalling pathway, which regulates protein synthesis, indicated by the reduced expression of all ribosomal proteins and other mTOR-dependent proteins: RPS6, VIM, LDHB and PPP2R1A. A protein-protein interaction network built from differentially expressed proteins in the combined dataset was significantly associated with schizophrenia-associated risk genes and with proteins regulating neural stem cell differentiation, cell adhesion and growth cones in the developing brain. This study demonstrates that despite the divergent age of onset, the proteomes of olfactory neural stem cells of adolescent- and adult-onset patients are remarkably similar. The dysregulated proteins in patient cells form a tightly interconnected protein-protein interaction network associated with mTOR signalling, protein translation, neurogenesis and axon growth - all key components of brain development.