Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

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 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.

Fig. 1. Neuronal pathways involving PDEs.

Schematic of the regulation of cAMP synthesis by Adenylate Cyclases (AC) or s(soluble)AC and of cGMP synthesis by guanylate cyclases (GC) or s(soluble)GC. Specific degradation of cAMP and cGMP is catalyzed by various PDEs whose specificity is shown. Targets of cAMP and cGMP are shown, as well as well-known neuronal pathways involved in neurodevelopment. Red arrows indicate inhibition while green arrows indicate activation. PKA cAMP-dependent Protein Kinase, Ca²⁺CaM Ca²⁺/calmodulin-dependent protein kinase II, EPAC Exchange Protein directly Activated by cAMP, Rap Ras-related protein, ERK Extracellular signal-Regulated Kinase, Raf rapidly accelerated fibrosarcoma, DARP32 dopamine- and cAMP-regulated neuronal phosphoprotein, PP1 protein phosphatase-1, MEK MitogEn-activated protein kinase Kinase, PKG cGMP-dependent protein kinase, PrKG protein kinase, cGMP-dependent, GSK3 glycogen synthase kinase 3, iNOS inducible nitric oxide synthase; NO nitric oxide, CREB cAMP response element-binding protein, CNP C-type natriuretic peptide.

Fig. 2. Structure, localization and implication of PDEs in brain disorders.

Left panel. The structure of each PDE subfamily is indicated by representing the various domains. Catalytic domain providing the substrate specificity: CAT. Regulatory domains: GAF: the name is related to the proteins it is found in: cGMP-specific phosphodiesterases, adenylyl cyclases and the bacterial transcription factor FhlA. Ca²⁺CaM Ca²⁺/calmodulin binding site; PAS Per-ARNT-Sim domain, that is a structural motif. TD transmembrane domain. REC cheY-homologous receiver domain. UCR upstream conserved region. ISD isoform specific domain. Regions that are submitted to alternative splicing have been indicated as VSD variant-specific domain. This domain is called PAT7 in PDE9A variants [148] Pγ is part of the PDE6 holoenzyme in rod. Isoforms originated by different genes exist and are indicated for the following subfamily: PDE1 (A, B, and C), PDE3 (A and B), PDE4 (A, B, C and D), PDE6 (A, B and C), PDE7 (A and B) and PDE8 (A and B). PDE2, PDE5, PDE9, PDE10 and PDE11 subfamilies are represented by only one member, namely PDE2A, PDE5A, PD9A, PDE10A and PDE11A. Splicing variants (in blue) of the same protein are indicated when they determine a specific subcellular localization. Middle panel. Localization of each isoform and variant is indicated [4, 6, 148]. Cy Cytosol, Me membrane; Mi mitochondria; Nu Nucleus. Right panel. Brain disorders involving the various PDEs are indicated according to all the genetic and pharmacological information considered in the text. Neurodevelopmental disorders are highlighted in red. AD Alzheimer disease; ASD autism spectrum disorder; BP bipolar disorder; DS down syndrome; HD Huntington disease; ID intellectual disability; FXS fragile X syndrome; MDD major depression disorder, RTT Rett syndrome, SCZ schizophrenia.