Biology subjects

Bradshaw, N. J.

Publications and source records attributed to Bradshaw, N. J..

3 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↗

bioRxiv2016

The NDE1 Genomic Locus Affects Treatment of Psychiatric Illness through Gene Expression Changes Related to MicroRNA-484

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the \"DISC1 network\". Here, we utilize gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, whilst prescription medication information has been collected over a ten-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2,908 probes (2,542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p=3.0x10-8), located on a non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

genetics↗