Abstract
Bipolar disorder is a highly heritable neuropsychiatric disorder affecting nearly 2.5% of the population. Prior genetic studies identified a panel of common and rare single-nucleotide polymorphisms associated with the disease that map to the first intron of the PDE10A gene. RNA sequencing of striatal brain tissue from bipolar and healthy control subjects identified a novel transcript of PDE10A, named PDE10A19, that codes for a PDE10A isoform with a unique N terminus. Genomic sequences that can encode the novel N terminus were conserved in other primates but not rodents. The RNA transcript was expressed at equal or greater levels in the human striatum compared with the two annotated transcripts, PDE10A1 and PDE10A2. The PDE10A19 transcript was detected in polysomal fractions; western blotting experiments confirmed that the RNA transcript is translated into protein. Immunocytochemistry studies using transfected mouse striatal and cortical neurons demonstrated that the PDE10A19 protein distributes to the cytosol, like PDE10A1, and unlike PDE10A2, which is associated with plasma membranes. Immunoprecipitation and immunocytochemical experiments revealed that the PDE10A19 isoform interacts physically with PDE10A2 and, when expressed at elevated levels, interferes with the plasma membrane localization of PDE10A2. These studies illustrate the complexity of PDE10A gene expression in the human brain and highlight the need to unravel the gene's complex and complete coding capabilities along with its transcriptional and translational regulation to guide the development of therapeutic agents that target the protein for the treatment of neuropsychiatric illness.
Highlights
Bipolar disorder (BD) is a neuropsychiatric disorder characterized by manic episodes intermixed with periods of depression.Individuals exhibiting mania experience periods of markedly elated moods, are distracted and tend to engage in impulsive and high-risk behaviors.[1]
Our results identified a series of common and rare single-nucleotide polymorphisms within the first large intron of the PDE10A gene as associated with BD, which generated great interest given the prominent expression of this enzyme in striatal cells,[17,18,19,20] the role of the striatum in coordinating and integrating cortical and dopaminergic inputs[21,22,23] and the promise of PDE10A as a pharmacological target for brain disorders including schizophrenia and BD.[24]
Our prior case–control study of 29 different genes comprising the cAMP signaling pathway identified seven common and eight rare nucleotide variants associated with BD that mapped to a 23 kb intronic region of the PDE10A gene.[12]
Summary
Bipolar disorder (BD) is a neuropsychiatric disorder characterized by manic episodes intermixed with periods of depression. We generated anti-peptide antibodies to the unique N termini of the three different PDE10A isoforms to assay their expression in both human tissue and transfected cells. Western blots were performed with cell lysates expressing each protein isoform (Figure 3) and probed with each individual anti-peptide antibody as well as with a monoclonal antibody against the HA epitope. In cells transfected with the HA-tagged PDE10A2 isoform, the anti-HA signal exhibited apparent membrane localization, whereas little or no signal was detected when the PDE10A2 anti-peptide antibody was used (Figures 4e–h). These results are consistent with previous western blots showing the absence or unexposed nature of the. PDE10A2 loses its significant enrichment to the membrane fraction when cotransfected with PDE10A19 (Supplementary Figures S7b and c), confirming the conclusion obtained from the immunocytochemical experiments
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