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Research sheds new light into the molecular basis of bipolar disorder

Bipolar disorder, also called manic-depressive disorder, is a neuropsychiatric disease that is characterized by intermixed phases of depression and mania. Often mistaken for Dr. Jekyll and Mr. Hyde syndrome which is a dissociative identity disorder, patients with bipolar disorder go through cycles of low motivation, listlessness, and comorbid conditions. Often, they experience the opposite, and go through maniac phases. During maniac phases, patients are in an elated mood, tend to take risky actions and are easily distracted. Bipolar disorder affects around 2.5% of the population and is highly heritable (Merikangas et al., 2007). Often the disease is diagnosed several years after the onset of symptoms. Treatment is difficult with a high recurrence rate and it usually involves lifelong maintenance treatment with mood stabilizers and antipsychotics. The molecular basis of this neuropsychiatric disorder is not well understood, but several studies suggest that cAMP signaling is disturbed in these patients (Dwivedi et al., 2008).

PDE10A19, a new PDE10A isoform

A recent study took a closer look at an enzyme that plays an important role in cAMP signaling, cyclic nucleotide phosphodiesterase 10 A (PDE10A). Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP and therefore, represent an important part of cyclic nucleotide signaling. Also, multiple single-nucleotide polymorphisms that are associated with bipolar disorder are located in the first intron of the PDE10A gene. MacMullen and colleagues from the department of Neuroscience at the Scripps Research Institute in Florida discovered a new PDE10A isoform, the PDE10A19 isoform. This isoform is conserved in primates but does not occur in rodents. Since bipolar disorder is a human-specific disease, this further implicates a possible role for PDE10A19 in neuropsychiatric diseases.

Role of PDE10A in bipolar disease

Two other PDE10A isoforms, PDE10A1 and PDE10A2, have been previously explored. Both isoforms are expressed in striatum cells of the human brain, but differ in their cellular localization. PDE10A1 is localized in the cytosol, whereas PDE10A2 is membrane-bound. Like PDE10A1, PDE10A19 is localized in the cytosol, but it is able to interact and to displace PDE10A2 from the membrane. Using Enzo’s Cyclic Nucleotide Phosphodiesterase assay kit, the authors demonstrated that all three isoforms are able to hydrolyze cAMP at a similar rate. The membrane-bound PDE10A2 has however an additional function, which might be important in neuropsychiatric disorders. Research suggests that PDE10A2 may inhibit the excitability of spiny neurons and thereby decrease their output. When the team compared PDEA10 expression in brain tissues from healthy control subjects and bipolar disorder patients, they indeed found that PDE10A2 transcripts were five-fold less abundant in bipolar disorder patients. This study showed that expression and regulation of PDE10A in human striatal neurons is more complicated than anticipated. Further research about the enzyme’s role in bipolar disorder might help to find new approaches for therapy.

Enzo life sciences provides Cyclic Nucleotide ELISA kits that have been highly published in peer-reviewed journals, which are species independent, and are suitable for various sample types. We also offer assays to measure Cyclic Nucleotide PDE Activity, cAMP and cGMP-dependent protein kinase products and Protein Kinase kits.

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Reference:

  1. C.M. MacMullen, et al. Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder. Transl. Psychiatry (2016) 6: 1.
  2. K.R. Merikangas, et al. The impact of comorbidity and mental and physical conditions on role disability in the US adult household population. Arch. Gen. Psychiatry (2007) 64: 1180.
  3. Y. Dwivedi, et al. Adenylyl cyclase-cyclicAMP signaling in mood disorders: role of the crucial phosphorylating enzyme protein kinase A. Neuropsychiatr. Dis. Treat. (2008) 4: 161.

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