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

Abstract

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.