Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease

Farmer, Reagan; Burbano, Steven D.; Patel, Neema S.; Sarmiento, Angelo; Smith, Abigail J.; Kelly, Michy P.

doi:10.1016/j.cellsig.2020.109592

Cited by 26 publications

(17 citation statements)

References 75 publications

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“…PDE11A4 also plays a role in systems consolidation, which has relevance for cognitive de cits [21]. Phosphodiesterases (PDEs) have been linked to mental processes of emotions, learning and memory, with implications in mood and cognitive disorders, including Huntington disease, Parkinson's disease and AD [22][23][24][25]. This evidence suggests that PDE11A plays a role in brain function and may also be involved in AD.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease

Qin

Zhou

Zuo

et al. 2021

Human Molecular Genetics

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To identify novel risk genes and better understand the molecular pathway underlying Alzheimer’s disease (ad), whole-exome sequencing (WES) was performed in 215 early-onset ad (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOad. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of ad patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease

Qin

Zhou

Zuo

et al. 2021

Human Molecular Genetics

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“…However, one should keep in mind that our measurements were performed in new born mice, and PDE expression levels change through mouse and human lifespan (Kelly et al, 2014;Hegde et al, 2016;Farmer et al, 2020). Since PDE10A remains the dominant form of PDE in the adult striatum, it is quite plausible that its key signalling function is maintained in adulthood.…”

Section: Pde Specificity On Different Camp Levelsmentioning

confidence: 99%

“…On the other hand, regulating the other PDEs such as PDE2A and PDE4 may provide a more subtle way to adjust the cAMP response and therefore tune PKA responses. For example, behavioral studies indicate that PDE2A inhibitors may be of interest for treating cognitive impairments including those associated with schizophrenia (Boess et al, 2004;Redrobe et al, 2014;Redrobe et al, 2015), while changes in striatal PDE2A expression level were correlated with psychiatric diseases (Farmer et al, 2020).…”

Section: Pdes As Therapeutic Targetsmentioning

confidence: 99%

Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones

Mota¹,

Bompierre²,

Betolngar³

et al. 2021

Preprint

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Dopamine in the striatum plays a crucial role in reward processes and action selection. Dopamine signals are transduced by D1 and D2 dopamine receptors which trigger mirror effects through the cAMP/PKA signalling cascade in D1 and D2 medium-sized spiny neurones (MSNs). Phosphodiesterases (PDEs), which determine the profile of cAMP signals, are highly expressed in MSNs, but their respective roles in dopamine signal integration remain poorly understood. We used genetically-encoded FRET biosensors to monitor at the single cell level the functional contribution of PDE2A, PDE4 and PDE10A in the changes of the cAMP/PKA response to transient and continuous dopamine in mouse striatal brain slices. We found that PDE2A, PDE4 and PDE10A operate on the moderate to high cAMP levels elicited by D1 or A2A receptor stimulation. In contrast, only PDE10A is able to reduce cAMP down to baseline in both type of neurones, leading to the dephosphorylation of PKA substrates. PDE10A is therefore critically required for dopamine signal integration in both D1 and D2 MSNs.

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“…Patients with bipolar disorder showed reduced PDE2A mRNA levels in the hippocampus, caudal entorhinal cortex, and striatum, while patients with SCZ, bipolar disorder, and major depressive disorder (MDD) showed reduced PDE2A mRNA levels in the amygdala. Furthermore, patients with schizophrenia have reduced PDE2A mRNA levels in the frontal cortical region [ 36 ]. Pde2a -KO mice have been generated but they are lethal during embryogenesis due to cardiac failure [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

2021

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Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with different substrate specificities. Their main function is to catalyze the hydrolysis of cAMP, cGMP, or both. cAMP and cGMP are two key second messengers that modulate a wide array of intracellular processes and neurobehavioral functions, including memory and cognition. Even if these enzymes are present in all tissues, we focused on those PDEs that are expressed in the brain. We took into consideration genetic variants in patients affected by neurodevelopmental disorders, phenotypes of animal models, and pharmacological effects of PDE inhibitors, a class of drugs in rapid evolution and increasing application to brain disorders. Collectively, these data indicate the potential of PDE modulators to treat neurodevelopmental diseases characterized by learning and memory impairment, alteration of behaviors associated with depression, and deficits in social interaction. Indeed, clinical trials are in progress to treat patients with Alzheimer’s disease, schizophrenia, depression, and autism spectrum disorders. Among the most recent results, the application of some PDE inhibitors (PDE2A, PDE3, PDE4/4D, and PDE10A) to treat neurodevelopmental diseases, including autism spectrum disorders and intellectual disability, is a significant advance, since no specific therapies are available for these disorders that have a large prevalence. In addition, to highlight the role of several PDEs in normal and pathological neurodevelopment, we focused here on the deregulation of cAMP and/or cGMP in Down Syndrome, Fragile X Syndrome, Rett Syndrome, and intellectual disability associated with the CC2D1A gene.

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Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease

Cited by 26 publications

References 75 publications

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease

Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

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