Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

Abstract

A robust body of evidence supports the concept that phosphodiesterase 10A (PDE10A) activity in the basal ganglia orchestrates the control of coordinated movement in human subjects. Although human mutations in the PDE10A gene manifest in hyperkinetic movement disorders that phenocopy many features of early Huntington’s disease, characterization of the maladapted molecular mechanisms and aberrant signaling processes that underpin these conditions remains scarce. Recessive mutations in the GAF-A domain have been shown to impair PDE10A function due to the loss of striatal PDE10A protein levels, but here we show that this paucity is caused by irregular intracellular trafficking and increased PDE10A degradation in the cytosolic compartment. In contrast to GAF-A mutants, dominant mutations in the GAF-B domain of PDE10A induce PDE10A misfolding, a common pathological phenotype in many neurodegenerative diseases. These data demonstrate that the function of striatal PDE10A is compromised in disorders where disease-associated mutations trigger a reduction in the fidelity of PDE compartmentalization.

The PDE-Opathies: Diverse Phenotypes Produced by a Functionally Related Multigene Family

“…Additionally, patients with PDE4D-associated acrodysostosis might benefit from therapy with PDE4selective inhibitors or allosteric activators. The chorea-like phenotypes caused by mutations in PDE10A or PDE2A inhibitors, and the localization of these enzymes to striatum, suggest that targeting PDE2 or PDE10 might be useful in the treatment of other striatal diseases, such as Huntington's chorea or Parkinson's disease [52].…”

“…Mutations in this region increase the interaction of PDE3A with 14.3.3-θ and produce an increase in PDE3A2-mediated cAMP hydrolysis [31,32,34]. Finally, the chorea-associated, dominantly inherited gain-of-function mutations in PDE10A map to a 'hot spot' within its GAF-B domain, causing localized protein misfolding that interferes with dimerization and regulation of the enzyme [29,30,51,52] (Figure 3B and Box 2). Given their dominant inheritance pattern, these gain-of-function mutations probably have a dominant-negative effect in cells, where the mutant, misfolded protein forms a dimer with its wild-type counterpart, thereby attenuating its function [52].…”

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

“…We do see upregulation of the genes encoding specific PDEs (PDE4B, PDE4D, and PDE7B) in Mardepodect-treated cells, but not PDE10A itself. The reason for this may be that the transcriptomics approach is measuring the emergence of a new steady-state within the drug-treated tumor cell population, involving more subtle regulation of localized cAMP-and cGMP-driven phosphorylation networks, as reported for PDE10A-regulated systems in the spiny neuron [138].…”

The Emerging Role of Phosphodiesterases in Movement Disorders

“… 8 However, recent evidence showed that heterozygous mutations in the GAF‐B domain may also drive misprocessing and misfolding of the protein. 98 Notably, another report demonstrated that loss‐of‐function biallelic PDE10A mutations, located in the GAF‐A domain and resulting in severe striatal PDE10A loss, are responsible for an infantile‐onset hyperkinetic movement disorder, indicating that loss of PDE10A activity is sufficient to cause chorea in humans. 52 Interestingly, patients with biallelic PDE10A mutations did not show the striking abnormalities of the striata observed on imaging of patients with dominant variants in the GAF‐B domain, indicating that dominant and recessive mutations have different pathogenic mechanisms.…”