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Role of Phosphodiesterases in the Pathophysiology of Neurodevelopmental Disorders

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Role of Phosphodiesterases in the Pathophysiology of Neurodevelopmental Disorders Molecular Psychiatry https://doi.org/10.1038/s41380-020-00997-9 REVIEW ARTICLE Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders 1 2 Sébastien Delhaye ● Barbara Bardoni Received: 4 July 2020 / Revised: 3 December 2020 / Accepted: 9 December 2020 © The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature 2021. This article is published with open access Abstract 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 1234567890();,: 1234567890();,: 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. Introduction Adenylate and guanylate cyclases (AC and GC) catalyze the synthesis of cAMP and cGMP starting from ATP and GTP, The family of phosphodiesterases respectively. In the brain, activation of AC is mediated by heterotrimeric G proteins upon activation of G protein- Cyclic adenosine monophosphate (cAMP) and cyclic gua- coupled receptors (GPCRs) by extracellular stimuli (Fig. 1), nosine monophosphate (cGMP) are second messengers that while soluble AC is directly activated by Ca2+ [2] (Fig. 1). regulate a variety of signaling pathways via direct interac- In the brain, soluble GC is mainly activated by nitric oxide tion with cAMP-dependent protein kinase A (PKA) and (NO) and transmembrane GC is activated by C-type cAMP-dependent protein kinase G (PKG), respectively [1]. natriuretic peptide (CNP) [3] (Fig. 1). cAMP and cGMP are hydrolized by phosphodiesterases (PDEs). The enzy- matic activity of PDEs was used as one of the initial pro- cesses providing evidence for the physiological importance Supplementary information The online version of this article (https:// of cAMP. Today, we know that PDEs catalyze the hydro- doi.org/10.1038/s41380-020-00997-9) contains supplementary ′ material, which is available to authorized users. lysis of the 3 phosphate bond of cAMP and cGMP to generate 5′ AMP and 5′ GMP, respectively [1]. Mammalian * Barbara Bardoni PDEs are classified in 11 subfamilies of proteins encoded [email protected] by 21 different genes, each one displaying multiple splice 1 Université Côte d’Azur, CNRS UMR7275, Institute of Molecular variants. These spliced variants often have different sub- and Cellular Pharmacology, 06560 Valbonne, France cellular localization (Fig. 2)[1, 4]. PDEs are divided into fi 2 Université Côte d’Azur, Inserm, CNRS UMR7275, Institute of three groups based on their speci city to cyclic nucleotides: Molecular and Cellular Pharmacology, 06560 Valbonne, France specific to cAMP (PDE4, PDE7, and PDE8), specificto S. Delhaye, B. Bardoni Raf Fig. 1 Neuronal pathways involving PDEs. Schematic of the reg- directly Activated by cAMP, Rap Ras-related protein, ERK Extra- ulation of cAMP synthesis by Adenylate Cyclases (AC) or s(soluble) cellular signal-Regulated Kinase, Raf rapidly accelerated fibro- AC and of cGMP synthesis by guanylate cyclases (GC) or s(soluble) sarcoma, DARP32 dopamine- and cAMP-regulated neuronal GC. Specific degradation of cAMP and cGMP is catalyzed by various phosphoprotein, PP1 protein phosphatase-1, MEK MitogEn-activated PDEs whose specificity is shown. Targets of cAMP and cGMP are protein kinase Kinase, PKG cGMP-dependent protein kinase, PrKG shown, as well as well-known neuronal pathways involved in neuro- protein kinase, cGMP-dependent, GSK3 glycogen synthase kinase 3, development. Red arrows indicate inhibition while green arrows iNOS inducible nitric oxide synthase; NO nitric oxide, CREB cAMP indicate activation. PKA cAMP-dependent Protein Kinase, Ca2+CaM response element-binding protein, CNP C-type natriuretic peptide. Ca2+/calmodulin-dependent protein kinase II, EPAC Exchange Protein cGMP (PDE5, PDE6, and PDE9), and hydrolyzing both the brain according to http://mousebrain.org/celltypes/ and cAMP and cGMP (PDE1, PDE2, PDE3, PDE10, and each PDE displays a specific expression pattern, as illu- PDE11). The PDEs in the last group have a higher affinity strated in Supplementary Table I [7]. A study by Lakics for one of the two cyclic nucleotides [1, 4]. This specificity et al. compared the expression levels of PDEs in different is associated with a “glutamine switch”, a highly conserved human brain regions [8]. In Supplementary Table II, we glutamine residue that regulates the binding of the cyclic summarize the results of this study indicating the 2–3 most nucleotide purine ring in the binding domain [5]. The highly expressed PDEs in each of the analyzed brain structural features of these enzymes, their regulatory regions. The expression of PDEs during brain development domains, and catalytic regions are common among isoforms is poorly studied. In Supplementary Table III, we sum- and are highly conserved across species. In each subfamily, marized the studies on this subject reported on Mouse Brain the main variable regions between each member are the N- Atlas https://mouse.brain-map.org/static/atlas. and C-terminal domain-containing elements for subcellular localization that is a critical element to define the specific Role of PDEs in the brain function of each PDE [4, 6]. In Fig. 2, the 11 subfamilies are shown and for each one the functional domains are In the brain, both cAMP and cGMP are essential during presented. Moreover, the activity of some PDEs depends on neurodevelopment as well as in maintaining synaptic cGMP (PDE2, PDE3, PDE5, and PDE6), while cAMP plasticity, and ultimately in learning and memory [9–11]. activates PDE10A [1] (Fig. 1). PDEs are expressed in the Indeed, it has been reported that the levels of both cAMP cells of all tissues. The precise spatiotemporal expression of and cGMP have critical roles in axon elongation and PDEs is crucial for the accurate regulation of cAMP and guidance [12, 13] and in regulating the morphology and cGMP levels. Indeed, all PDEs appear to be expressed in growth of dendritic spines, where they have opposite Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders PDE1 VSDCaM CaM CAT VSD PDE2 VSD GAF A GAF B CAT PDE3 TD CAT PDE4 VSD UCR1 UCR2 CAT PDE5 VSD GAF A GAF B CAT ISD P PDE6 CAT VSD PDE7 VSD CAT ISD PDE8 VSD REC PAS CAT PDE9 Pat7 CAT PDE10 GAF A GAF B CAT PDE11 GAF A GAF B CAT Fig. 2 Structure, localization and implication of PDEs in brain (A and B) and PDE8 (A and B). PDE2, PDE5, PDE9, PDE10 and disorders. Left panel. The structure of each PDE subfamily is indi- PDE11 subfamilies are represented by only one member, namely cated by representing the various domains. Catalytic domain providing PDE2A, PDE5A, PD9A, PDE10A and PDE11A. Splicing variants (in the substrate specificity: CAT. Regulatory domains: GAF: the name is blue) of the same protein are indicated when they determine a specific related to the proteins it is found in: cGMP-specific phosphodies- subcellular localization. Middle panel. Localization of each isoform terases, adenylyl cyclases and the bacterial transcription factor FhlA. and variant is indicated [4, 6, 148]. Cy Cytosol, Me membrane; Mi Ca2+CaM Ca2+/calmodulin binding site; PAS Per-ARNT-Sim domain, mitochondria; Nu Nucleus. Right panel. Brain disorders involving the that is a structural motif. TD transmembrane domain. REC cheY- various PDEs are indicated according to all the genetic and pharma- homologous receiver domain. UCR upstream conserved region. ISD cological information considered in the text. Neurodevelopmental isoform specific domain. Regions that are submitted to alternative disorders are highlighted in red. AD Alzheimer disease; ASD autism splicing have been indicated as VSD variant-specific domain. This spectrum disorder; BP bipolar disorder; DS down syndrome; HD domain is called PAT7 in PDE9A variants [148]Pγ is part of the Huntington disease; ID intellectual disability; FXS fragile X syn- PDE6 holoenzyme in rod. Isoforms originated by different genes exist drome; MDD major depression disorder, RTT Rett syndrome, SCZ and are indicated for the following subfamily: PDE1 (A, B, and
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