An emerging approach to studying major mental illness is through proteostasis, with the identification of several proteins that form insoluble aggregates in the brains of patients. One of these is Disrupted in Schizophrenia 1 (DISC1), a neurodevelopmentally-important scaffold protein, and product of a classic schizophrenia risk gene. DISC1 aggregates have been detected in post mortem brain tissue from patients with schizophrenia, bipolar disorder and major depressive disorder, as well as various model systems, although the mechanism by which it aggregates is still unclear. Aggregation of two other proteins implicated in mental illness, TRIOBP-1 and NPAS3, was shown to be dependent on very specific structural regions of the protein. We therefore looked at the domain structure of DISC1, and investigated which structural elements are key for its aggregation. While none of the known structured DISC1 regions (named D, I, S and C respectively) formed aggregates individually when expressed in neuroblastoma cells, the combination of the D and I regions, plus the linker region between them, formed visible aggregates. Further refinement revealed that a region of approximately 30 amino acids between these two regions is critical for aggregation, and deletion of this region is sufficient to abolish the aggregation propensity of DISC1. This finding from mammalian cell culture contrasts with the recent determination that the C-region of DISC1 can aggregate in vitro, although some variations of the C-terminal of DISC1 could aggregate in our system. It therefore appears likely that DISC1 aggregation, implicated in mental illness, can occur through at least two distinct mechanisms.
Keywords: DISC1; Domain structure; Protein aggregation; Proteinopathy; Proteostasis; Psychiatric illness.
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