engleski

Aggregation of the protein TRIOBP-1 in schizophrenia

We have proposed that, in analogy to major neurodevelopmental conditions such as Alzheimer’s disease and Parkinson’s disease, chronic mental illness may be characterised, at least in part, by the presence of insoluble micro-aggregates of specific misfolded proteins in the brain, as the result of aberrant protein homeostasis. In order to test this hypothesis, we took the pooled insoluble fraction (“aggregome”) of brain homogenate samples from patients with schizophrenia and used them to immunise a mouse. After generating monoclonal antibodies from this animal, one clone was identified which was able to differentiate between the pooled schizophrenia brain aggregomes and an equivalent sample from control individuals. Following high throughput antigen screening, it was determined that this antibody recognised the actin-polymerising protein TRIOBP-1. This strongly suggests that TRIOBP-1 may aggregate specifically in the brains of a least a subset of patients with schizophrenia. Replication experiments to confirm this are currently underway. We have confirmed that the TRIOBP-1 protein, but not TRIOBP-4, an alternative splice variant sharing no sequence with TRIOBP-1, was capable of forming aggregates in neuroblastoma cells and rat primary neurons. This was true both when the protein was exogenously over-expressed, and also for the endogenous protein in the cells, which showed an increased aggregation propensity when the cells were post-mitotic, consistent with the build-up of aggregated protein in the brain. Over-expression of aggregating TRIOBP-1 in Neuroscreen-1 cells led to changes in the cell morphology, indicating that TRIOBP-1 aggregates may play an active role in development, rather than simply being a by-product of cellular processes with are disrupted in schizophrenia. Finally, we have now identified regions of the TRIOBP-1 which are responsible for its propensity to spontaneously form aggregates, and are mapping their significance to the normal structural architecture of the protein. Through understanding the mechanisms by which TRIOBP-1 aggregates, we aim to elucidate a novel aspect of the underlying cellular pathology of schizophrenia, one whose causes could be potentially influenced by both genetic and environmental effects.

TRIOBP ; Tara ; Aggregation ; Mental illness ; Schizophrenia

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