engleski

Aggregation of specific proteins as a biological component of chronic mental illness

Introduction: Major mental illnesses such as schizophrenia and the affective disorders are devastating and often chronic, but our knowledge of their biomedical basis is limited, in large part because of the complex and heterogeneous nature of the genetics that govern them. As an alternative, we took inspiration from other chronic neurological disorders in which insoluble aggregates of specific proteins accumulate in the brain. Aim: To identify proteins which may form insoluble aggregates specifically in the brains of at least a subset of patients with major mental illnesses, and notably in schizophrenia. Having identified such potential proteins, the next aim is to investigate the mechanisms by which this occurs. Methods: Initial tests were performed on brain tissue samples from patients with schizophrenia or control individuals. The insoluble protein fraction of these were isolated biochemically and investigated for the presence of specific proteins. Follow up experiments were performed by expressing putative aggregating proteins in mammalian cell and neuronal cultures. Aggregation propensity was determined both through biochemical isolation of the insoluble protein fraction and also visually using immunofluorescence microscopy. Results: Initial tests revealed both established mental illness risk proteins (such as DISC1) and novel ones (such as TRIOBP-1) to potentially aggregate in mental illness. Notably, these proteins also aggregate upon expression in mammalian cell lines and primary neuron cultures, often being dependent on a very specific structural part of the protein. Such “aggregation motifs” imply that the proteins may aggregate in very specific cellular circumstances, potentially associated with major mental illness. Conclusions: Protein aggregation may be a component of chronic mental illnesses in at least a subset of patients, and several putative aggregating proteins have been identified. Further investigation is now required to confirm this in larger patient samples, and to elucidate further both the biological causes and pathological consequences of these aggregates.

Cell biology, Molecular Biology, Protein Aggregation, Schizophrenia

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