engleski

Chronic mental illnesses as disorders of protein aggregation

Introduction/Objectives: In spite of their devastating effect both on individual patients and society as a whole, the biology of major mental illnesses such as schizophrenia, bipolar disorder and major depressive disorder remain poorly understood. Genome wide association approaches have been successful in identifying many risk genes, however the effect size of any individual variant remains small. We have therefore proposed the study of proteins involved in these conditions, as a complementary approach to probing their underlying biology. Specifically, we have taken inspiration from the formation of protein insoluble aggregates in many neurodegenerative conditions, and hypothesised that similar, perhaps more subtle, defects in protein homeostasis may also occur in the brains of patients with chronic instances of major mental illness. Participants, Materials/Methods: Initial identification of putative aggregating proteins was made in brain samples from patients with schizophrenia, bipolar disorder and/or major depression, plus control individuals. The insoluble protein fractions of these tissue were purified biochemically, and then probed for protein content. This involved either Western blotting for products of known mental illness risk genes, or else using proteomic-based approaches to identify novel proteins. Following these initial identifications, further characterisation of the proteins has occurred in both cell and rodent models of the conditions. Results: To date, five proteins have been identified which seem to form insoluble aggregates specifically in the brains of patients. Three of these, DISC1, dysbinsin-1B and NPAS3, are products of previously studied risk genes, while the remaining two, CRMP1 and TRIOBP-1, were identified through hypothesis free proteomics approaches. These are all brain-expressed proteins containing stretches of disordered secondary structure. Functionally, they are each involved in either synaptic function, cytoskeletal regulation or both. In many instances, one isoform or variant of the protein readily forms aggregates in cell culture and/or animal models, while others do not. For several of the proteins, specific regions of the protein have been shown to be essential for aggregation. Further characterisation of the aggregation propensity of these proteins is ongoing. Conclusions: While still in its infancy as a field, the study of major mental illnesses as proteinopathies is showing promise, with multiple candidate proteins implicated as potentially aggregating specifically in the brains of patients. Studies in larger brain collections, as well as further biochemical characterisation of the proteins, is now required to determine their ultimate relevance for diagnosis and/or treatment of chronic mental illness.

Schizophrenia ; Mental illness ; Protein aggregation ; Proteinopathy

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