Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages

Abstract

Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P=2.66 × 10−10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P=3.07 × 10−19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the central nervous system. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter and cytoskeletal signalling occurs during early fetal brain development of BD I patients.

Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder

“…For this purpose, we cultured BD and control NSC for 5 days, prior protein sampling preparation. 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).…”

“…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. In a previous study, 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.…”

Tumorigenic effects of TLX overexpression in HEK 293T cells

“…Dissociation curve analysis confirmed the presence of a single amplicon. Normalization and data analysis were performed in GenEx 6.1 (TATAA Biocenter), as previously described …”

From the Psychiatrist’s Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish

“…In addition to altered neurodevelopmental pathways ( Section 6.1 ), neuronal activity ( Section 6.2 ), lithium response pathways ( Section 6.3 ), and microRNAs (see above), a recent study [ 71 ] suggests an early onset of inflammatory processes in BD. Vizlin-Hodzic et al generated six BD and four control iPSCs from adipocyte cells reprogrammed through episomal expression vectors ( Table 1 ).…”