Neurology Central

Disturbances in protein regulation offer new possibilities for schizophrenia treatment

Several studies involving scientists from Griffith University’s Eskitis Institute for Drug Discovery (QLD, Australia), the Royal College of Surgeons in Ireland (Dublin, Ireland) and University College Dublin (Ireland) have published findings that implicate dysregulated protein synthesis in the pathology of schizophrenia. The two studies, which both utilized adult stem cells of schizophrenia patients – comparing them with healthy control stem cells – observed increased protein levels but decreased rates of protein synthesis. The apparently contradictory results of the studies implicate the importance of disturbed protein regulation in the pathology of schizophrenia and indicate a cell-specific pathology for the disease. The results were published recently in Translational Psychiatry.

“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,” commented Alan Mackay-Sim (Eskitis Institute).

“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.”

In the first study, over 1000 proteins in the stem cells of nine schizophrenia patients and nine healthy patients were evaluated. Analyses revealed that there was a reduction in 17 ribosomal proteins as well as a significant decrease in the rate of protein synthesis in the schizophrenia patients’ stem cells. After further scrutiny of proteomic and transcriptomic data, researchers demonstrated that there were disturbances in several protein translational pathways, such as mTOR, eIF2α and eIF4α, with genome-wide association data supporting the role of these pathways in the disease at a genomic level.

“It is now becoming clearer that many small genetic variants are linked because they share control of cellular functions, in this case protein synthesis,” remarked Mackay-Sim.

“This work helps make sense of the rapid advances in genetics that have identified hundreds of risk genes for schizophrenia.”

Further research involving Mackay-Sim also appeared within the same issue of Translational Psychiatry, highlighting potentially contradictory results . In this second study, induced pluripotent stem cells taken from adult patients with schizophrenia were utilized to generate neural progenitor cells. These neural progenitor cells, which progress into brain cells during human embryonic development, were determined to exhibit increased total protein levels (significantly, higher levels of ribosomal translation initiation and elongation factor proteins) as well as an increased rate of protein synthesis compared with controls.

“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,” commented 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.”

Both studies present novel insight into the cellular pathology of schizophrenia, indicating a role for disturbance in protein regulation. This disruption in the global translation and synthesis of proteins within the stem cells of schizophrenic patients offers potential explanations for mechanisms of disease progression and provides possible avenues of exploration for future drug development.

Sources: Griffith University Press Release via EurekAlert; English JA, Fan Y, Föcking M et al. Reduced protein synthesis in schizophrenia patient-derived olfactory cells. Translational Psychiatry. 5 (10), e663 doi:10.1038/tp.2015.119 (2015) (Epub ahead of print); Topol A, English JA, Flaherty E et al. Increased abundance of translation machinery in stem cell–derived neural progenitor cells from four schizophrenia patients. Translational Psychiatry. 5 (10), e662 doi:10.1038/tp.2015.118 (2015) (Epub ahead of print).