engleski

Investigating the mechanisms of TRIOBP-1 aggregation in mental illness

Schizophrenia is a chronic mental illness, characterized by severe symptoms such as delusions, hallucinations, disorganized speech, lack of motivation, and unpredictable behavior. The development of schizophrenia is caused by genetic and environmental factors. The complexity of these factors has made it difficult to develop new methods for the successful treatment of patients. Recent research has shown that disruption of proteostasis may also impact the progression of schizophrenia. Disruption in proteostasis causes certain proteins to misfold and therefore aggregate if the cell fails to degrade them. Aggregation is a process in which insoluble large structures known as aggregates are formed. So far, five proteins have been identified that may aggregate in schizophrenia. Among these five is TRIO and F-actin-binding protein (TRIOBP- 1), our protein of interest. Using C-terminally truncated constructs, it was discovered that the critical region for aggregation of TRIOBP-1 is located in the central region of the protein. As a next step, we expressed different truncated variants of TRIOBP-1 in neuroblastoma cells and are using immunofluorescent microscopy to visualize aggregation. In this way, we have now narrowed down the critical region for aggregation to a sequence of less than 10 amino acids. Our most recent findings suggest that the presence of the PH domain at the N-terminus causes aggregation, indicating that TRIOBP-1 has two aggregation domains. By generating a TRIOBP-1 mutant with the minimal number of mutations required to prevent aggregation we will be able to generate model systems for studying TRIOBP-1 aggregation, the first of which will be Drosophila melanogaster. This will allow us to better understand the role of TRIOBP-1 in the progression of schizophrenia.

Schizophrenia ; TRIOBP-1 ; Protein aggregations ; mental illness

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