Abstract
We have previously proposed that specific proteins may form insoluble aggregates as a response to an illness-specific proteostatic dysbalance in a subset of brains from individuals with mental illness, as is the case for other chronic brain conditions. So far, established risk factors DISC1 and dysbindin were seen to specifically aggregate in a subset of such patients, as was a novel schizophrenia-related protein, CRMP1, identified through a condition-specific epitope discovery approach. In this process, antibodies are raised against the pooled insoluble protein fractions (aggregomes) of post mortem brain samples from schizophrenia patients, followed by epitope identification and confirmation using additional techniques. Pursuing this epitope discovery paradigm further, we reveal TRIO binding protein (TRIOBP) to be a major substrate of a monoclonal antibody with a high specificity to brain aggregomes from patients with chronic mental illness. TRIOBP is a gene previously associated with deafness which encodes for several distinct protein species, each involved in actin cytoskeletal dynamics. The 3′ splice variant TRIOBP-1 is found to be the antibody substrate and has a high aggregation propensity when over-expressed in neuroblastoma cells, while the major 5′ splice variant, TRIOBP-4, does not. Endogenous TRIOBP-1 can also spontaneously aggregate, doing so to a greater extent in cell cultures which are post-mitotic, consistent with aggregated TRIOBP-1 being able to accumulate in the differentiated neurons of the brain. Finally, upon expression in Neuroscreen-1 cells, aggregated TRIOBP-1 affects cell morphology, indicating that TRIOBP-1 aggregates may directly affect cell development, as opposed to simply being a by-product of other processes involved in major mental illness. While further experiments in clinical samples are required to clarify their relevance to chronic mental illness in the general population, TRIOBP-1 aggregates are thus implicated for the first time as a biological element of the neuropathology of a subset of chronic mental illness.
Highlights
Schizophrenia, along with the related conditions bipolar disorder and major depression, are devastating and often chronic conditions with a strong genetic basis that has only partially been explained to date by means of conventional and genome-wide genetic association and linkage studies [1]
In Alzheimer’s disease, by comparison, significantly more progress in understanding the condition’s pathological mechanism has arisen through the identification of mechanisms of assembly of the Ab peptides into plaques [2], characteristic of the disease, than through traditional genetic approaches [3]. While no such large plaques or aggregated protein structures exist for major mental illnesses such as schizophrenia, we have previously put forward the hypothesis that the formation of micro-aggregates or assemblies of specific proteins within the neurons and/or other cells of the brain may be hallmark of such psychiatric illnesses and account for the chronic nature of these conditions in some patients [4]
It was confirmed that antibody 6H11 was able to recognise recombinant human TRIO binding protein (TRIOBP)-1 fused to Maltose Binding Protein (MBP), but not MBP alone and detected the same major 70 kDa band as a polyclonal antibody against TRIOBP in neuroblastoma cells
Summary
Schizophrenia, along with the related conditions bipolar disorder and major depression, are devastating and often chronic conditions with a strong genetic basis that has only partially been explained to date by means of conventional and genome-wide genetic association and linkage studies [1]. In Alzheimer’s disease, by comparison, significantly more progress in understanding the condition’s pathological mechanism has arisen through the identification of mechanisms of assembly of the Ab peptides into plaques [2], characteristic of the disease, than through traditional genetic approaches [3] While no such large plaques or aggregated protein structures exist for major mental illnesses such as schizophrenia, we have previously put forward the hypothesis that the formation of micro-aggregates or assemblies of specific proteins within the neurons and/or other cells of the brain may be hallmark of such psychiatric illnesses and account for the chronic nature of these conditions in some patients [4]. Proteomic approach we used the identification of a proteostatic signature represented by the accumulation of specific insoluble proteins to identify molecular circuitry associated with failure in cognitive features [8]
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