Biology subjects

Zaharija, B.

Publications and source records attributed to Zaharija, B..

2 recordsLinked to original sources

bioRxiv2023

Aggregation of Disrupted in Schizophrenia 1 arises from a central region of the protein

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 the product of a classic schizophrenia risk gene. DISC1 was seen to aggregate in post mortem tissue from patients with schizophrenia, bipolar disorder and major depressive disorder, as well as in a variety of model systems, although the mechanism by which it does so 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 to the recently determined domain structure of DISC1, and investigated which structural elements were key for its aggregation. While none of the known 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 to aggregation, with deletion of this region from full length DISC1 sufficient to abolish its aggregation propensity. This finding from mammalian cell culture contrasts with the recent determination that the extreme C-terminal of DISC1 can aggregate in vitro, although we did see some indication that combinations of C-terminal DISC1 regions can also aggregate in our system. It therefore appears likely that DISC1 aggregation, implicated in mental illness, can occur through at least two distinct mechanisms.

cell biology↗

bioRxiv2023

Co-aggregation and parallel aggregation of specific proteins in major mental illness

BackgroundDisrupted proteostasis is an emerging area of research into major depressive disorder. Several proteins have been implicated as specifically forming aggregates in the brains of subsets of patients with psychiatric illnesses, these proteins include CRMP1, DISC1, NPAS3 and TRIOBP-1. It is unclear, however, whether these normally aggregate together in the same individuals, and, if so, whether each protein aggregates independently of each other ("parallel aggregation") or if the proteins physically interact and aggregate together ("co-aggregation"). Materials and methodsPost mortem insular cortex samples from major depressive disorder and Alzheimers disease patients, suicide victims and control individuals had their insoluble fractions isolated and tested by Western blotting to determine which of these proteins are insoluble, and therefore likely aggregating. The ability of the proteins to co-aggregate (directly interact and form common aggregate structures) was tested by systematic pairwise expression in SH-SY5Y neuroblastoma cells, examined by immunofluorescent microscopy. ResultsMany individuals displayed multiple insoluble proteins in the brain, although not enough to imply interaction between the proteins. Cell culture analysis revealed that only a few of the proteins analyzed can consistently co-aggregate with each other: DISC1 with CRMP1 and TRIOBP-1. DISC1 was able to induce aggregation of full length TRIOBP-1, but not its domains expressed individually. ConclusionsWhile specific proteins are capable of co-aggregating, and appear to do so in the brains of individuals with mental illness, and potentially also with suicidal tendency, it is more common for such proteins to aggregate in a parallel manner, through independent mechanisms.

neuroscience↗