Abstract
Identification of causative genetic variants leading to the development of bipolar disorder (BD) could result in genetic tests that would facilitate diagnosis. A better understanding of affected genes and pathways is also necessary for targeting of genes that may improve treatment strategies. To date several susceptibility genes have been reported from genome-wide association studies (GWAS), but little is known about specific variants that affect disease development. Here, we performed quantitative proteomics and whole-genome sequencing (WGS). Quantitative proteomics revealed NLRP2 as the most significantly up-regulated protein in neural stem cells and mature neural cells obtained from BD-patient cell samples. These results are in concordance with our previously published transcriptome analysis. Furthermore, the levels of FEZ2 and CADM2 proteins were also significantly differentially expressed in BD compared to control derived cells. The levels of FEZ2 were significantly downregulated in neural stem cells (NSC) while CADM2 was significantly up-regulated in mature neuronal cell culture. Promising novel candidate mutations were identified in the ANK3, NEK3, NEK7, TUBB, ANKRD1, and BRD2 genes. A literature search of candidate variants and deregulated proteins revealed that there are several connections to microtubule function for the molecules putatively involved. Microtubule function in neurons is critical for axon structure and axonal transport. A functional dynamic microtubule is also needed for an advocate response to cellular and environmental stress. If microtubule dynamics is compromised by mutations, it could be followed by deregulated expression forming a possible explanation for the inherited vulnerability to stressful life events that have been proposed to trigger mood episodes in BD patients.
Highlights
Bipolar disorder (BD) is a severe chronic psychiatric disorder, affecting >1% of the population worldwide[1]
Quantitative proteomics We performed quantitative proteomics using tandem mass tags (TMT) to quantify protein levels in neural stem cells (NSC) and mature 3D neural aggregate cultures obtained from five BD and four control-induced pluripotent stem cell (iPSC) cell lines
In line with our transcriptome analyses[8], NACHT, LRR, and PYD-containing protein 2 (NLRP2) were most significantly up-regulated in NSCs obtained from BD-patient cells (Fig. 2)
Summary
Bipolar disorder (BD) is a severe chronic psychiatric disorder, affecting >1% of the population worldwide[1]. Despite the complexity of the disease, we hypothesized that because of its high heritability it might be possible to identify common mis-regulated genes or pathways during neural development in BD. We integrated induced pluripotent stem cell (iPSC) technology[7] with RNA-seq to investigate differences in the global transcriptome between BD patients and healthy controls[8] using iPSC and neural stem cells (NSC)[9]. We found the NLRP2 gene to be the most significant differentially expressed gene with a clear difference in expression for all cases and controls. The NLRP2 gene is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family. Members of this family are thought to be important regulators of immune responses. Post-mortem frontal cortex obtained from BD patients has been reported to show a high amount of a protein closely related to NLRP2, namely NLRP310, in comparison to bio-samples from healthy individuals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
