title: 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.
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Vizlin-Hodzic
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhai
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Oncology Laboratory, Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Illes
authors.affiliation: Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Södersten
authors.affiliation: Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Truvé
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: T Z
authors.initials: TZ
authors.lastname: Parris
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: P K
authors.initials: PK
authors.lastname: Sobhan
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Salmela
authors.affiliation: Institute of Biomedicine, Department of Medical Genetics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: S T
authors.initials: ST
authors.lastname: Kosalai
authors.affiliation: Institute of Biomedicine, Department of Medical Genetics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Kanduri
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Strandberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Seth
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: T O
authors.initials: TO
authors.lastname: Bontell
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Hanse
authors.affiliation: Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Ågren
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Oncology Laboratory, Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Funa
mesh_terms: D000199:Actins / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017667:Adipocytes; D017668:Age of Onset; D051017:Apoptosis Regulatory Proteins; D001714:Bipolar Disorder / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000276:immunology* / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics; D007249:Inflammation; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000276:immunology* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D008840:Microfilament Proteins; D009124:Muscle Proteins; C495732:NLRP2 protein, human; C051615:transgelin