Research helps make sense of rapid advances in genetics that have identified hundreds of risk genes.
Stem cells from adult schizophrenia patients form new proteins more slowly than those from healthy people, according to new research.
The findings are enhancing understanding of how schizophrenia affects the workings of the brain, and open the way to new approaches for future drug therapies.
Involving scientists from Griffith University’s Eskitis Institute for Drug Discovery, the Royal College of Surgeons in Ireland and University College Dublin, the research is published online in the journal Translational Psychiatry.
According to the Eskitis Institute’s Professor Emeritus Alan Mackay-Sim, analysis of almost 1000 proteins in patients’ stem cells indicated their cellular machinery for making new proteins was reduced, with the rate of protein synthesis greatly impaired.
“Proteins are the workhorses of all cells and make up most of a cell’s structure and functions,” says Professor Mackay-Sim, whose Griffith team included Dr Yongjun Fan and Mr Nicholas Matigian.
“Cells live in a very dynamic environment and protein synthesis, which is so important for brain development, function and learning, is impacted by environmental and genetic factors.
“It is now becoming clearer that many small genetic variants are linked because they share control of cellular functions, in this case protein synthesis.
“If protein synthesis is altered even slightly, many cell functions would also be subtly changed. This could affect brain development and adult brain function in schizophrenia.
“This work helps make sense of the rapid advances in genetics that have identified hundreds of risk genes for schizophrenia.”
Interestingly, the same issue of Translational Psychiatry reports contrasting findings from a second research collaboration, also involving Professor Mackay-Sim, University College Dublin and a laboratory in the US.
This study used a different kind of stem cell generated from people with schizophrenia, namely induced pluripotent stem cells.
These are genetically engineered from skin cells and stimulated to turn into stem cells resembling the neural progenitor cells that give rise to the brain in the developing human embryo.
When the proteins from these cells were analysed, the patients’ cells were found to have more protein-making machinery and also made proteins more quickly than cells from healthy controls.
“However, while on the surface this seems like a contradiction, the two studies support each other by showing that the regulation of protein synthesis is subtly disturbed in the cells of people with schizophrenia,” says Professor Mackay-Sim.
“The studies seem to show that the on/off switch for protein synthesis may be altered in different cells or at different life stages in schizophrenia.
“This provides many ways in which brain development and function is altered in schizophrenia, and many routes for the ways in which genes and the environment interact to cause schizophrenia.”
About this schizophrenia research
Source: Michael Jacobson – Griffith University Image Source: The image is in the public domain Original Research: Full open access research for “Reduced protein synthesis in schizophrenia patient-derived olfactory cells” by J A English, Y Fan, M Föcking, L M Lopez, M Hryniewiecka, K Wynne, P Dicker, N Matigian, G Cagney, A Mackay-Sim and D R Cotter in Translational Psychiatry. Published online October 20 2015 doi:10.1038/tp.2015.119
Full open access research for “Increased abundance of translation machinery in stem cell–derived neural progenitor cells from four schizophrenia patients” by A Topol, J A English, E Flaherty, P Rajarajan, B J Hartley, S Gupta, F Desland, S Zhu, T Goff, L Friedman, J Rapoport, D Felsenfeld, G Cagney, A Mackay-Sim, J N Savas, B Aronow, G Fang, B Zhang, D Cotter and K J Brennand in Translational Psychiatry. Published online October 20 2015 doi:10.1038/tp.2015.118
Reduced protein synthesis in schizophrenia patient-derived olfactory cells
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.
“Reduced protein synthesis in schizophrenia patient-derived olfactory cells” by J A English, Y Fan, M Föcking, L M Lopez, M Hryniewiecka, K Wynne, P Dicker, N Matigian, G Cagney, A Mackay-Sim and D R Cotter in Translational Psychiatry. Published online October 20 2015 doi:10.1038/tp.2015.119
Increased abundance of translation machinery in stem cell–derived neural progenitor cells from four schizophrenia patients
The genetic and epigenetic factors contributing to risk for schizophrenia (SZ) remain unresolved. Here we demonstrate, for the first time, perturbed global protein translation in human-induced pluripotent stem cell (hiPSC)-derived forebrain neural progenitor cells (NPCs) from four SZ patients relative to six unaffected controls. We report increased total protein levels and protein synthesis, together with two independent sets of quantitative mass spectrometry evidence indicating markedly increased levels of ribosomal and translation initiation and elongation factor proteins, in SZ hiPSC NPCs. We posit that perturbed levels of global protein synthesis in SZ hiPSC NPCs represent a novel post-transcriptional mechanism that might contribute to disease progression.
“Increased abundance of translation machinery in stem cell–derived neural progenitor cells from four schizophrenia patients” by A Topol, J A English, E Flaherty, P Rajarajan, B J Hartley, S Gupta, F Desland, S Zhu, T Goff, L Friedman, J Rapoport, D Felsenfeld, G Cagney, A Mackay-Sim, J N Savas, B Aronow, G Fang, B Zhang, D Cotter and K J Brennand in Translational Psychiatry. Published online October 20 2015 doi:10.1038/tp.2015.118