engleski

TRIOBP as a NDE1-interaction partner which may form insoluble aggregates in schizophrenia

In an effort to identify potential biological markers of major mental illness, we have previously proposed the identification of specific proteins which form insoluble aggregates in a condition-specific manner, as is the case for other neurological illnesses. To this effect, we have determined DISC1 (Disrupted in Schizophrenia 1) to specifically aggregate in a subset of patients with major mental illness as well as identifying a novel schizophrenia-related protein, CRMP1 (Collapsin Response Mediator Protein 1). This latter protein was identified through a process of raising antibodies against the pooled insoluble fractions of post mortem brain samples from schizophrenia patients and followed by epitope identification and confirmation using genetic techniques. In this study we pursue this epitope discovery paradigm further, revealing TRIO binding protein (TRIOBP) to be a major substrate of a monoclonal antibody with a high specificity to schizophrenia brain aggregomes. The TRIOBP gene encodes for several distinct protein species, however only those deriving from the 3’ end of the gene, as typified by the actin-bundling TRIOBP1, could be seen to form aggregates in neuroblastoma cell lines, either due to over-expression of the protein or spontaneously following differentiation of the cells. We have previously determined that the expression level of TRIOBP is dependent on a haplotype of the NDE1 (Nuclear Distribution Element 1) locus, a finding which we were able to replicate within schizophrenia cohorts. NDE1 is an important neurodevelopmental protein which has been linked to schizophrenia via genetic association studies, copy number variation and interaction with the DISC1 protein. Intriguingly, we find the TRIOBP and NDE1 proteins to also be interaction partners within the cell, suggesting that the NDE1 locus may alter the function of TRIOBP both at the transcriptional and protein level. Potential mechanisms for this will be discussed. Thus, in addition to identifying a potential new protein in schizophrenia pathology, we also reveal how it may fit into the wider picture of established mental illness related pathways.

TRIOBP ; Tara ; Aggregation ; Mental illness ; Schizophrenia

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