engleski

Protein aggregation of TRIOBP-1 in patients with schizophrenia

Schizophrenia is a devastating and chronic mental illness with a highly complex and heterogeneous genetic basis. As an alternative approach to studying its biological basis, we have been investigating the existence of specific unfolded or aggregated proteins in the brains of patients. This is partially analogous to aggregated protein depos - its in neurodegenerative conditions such as Alzheimer’s disease or Parkinson’s disease. Through purification of the insoluble protein fraction of brain samples from schizophrenia patients, and using this to immunize a mouse, we have been able to isolate a monoclonal antibody that specifically detects the insoluble protein fraction of brain samples from schizo - phrenia patients over an equivalent preparation derived from control individuals. This antibody was subsequently shown to have as an antigen the actin-binding protein TRIOBP-1, implying that TRIOBP-1 may exist as an insoluble or aggregated species in the brains of at least a subset of patients with a major mental illness. Further investigation in cell lines and primary neurons has confirmed that the TRIOBP-1 protein has an intrinsic tendency to form aggregate structures when expressed in these cells and that the aggregates im - pact upon neurite outgrowth. Furthermore, this aggregation propensity of TRIOBP-1 is dependent on a very specific motif within the protein, currently isolated to just 9 amino acids, suggesting that a specific cellular mechanism is required for its aggregation. Through further analysis of the mechanism and consequences of TRIOBP-1 aggrega - tion in schizophrenia, it is hoped that insight can be gained into the biological basis of this devastating psychiatric condition.

mental illness ; protein aggregation ; protein misfolding ; psychiatric illness ; schizophrenia

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