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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-01, Vol.117 (1), p.677-688
• Main Authors: Tejeda, Gonzalo S., Whiteley, Ellanor L., Deeb, Tarek Z., Bürli, Roland W., Moss, Stephen J., Sheridan, Eamonn, Brandon, Nicholas J., Baillie, George S.
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - genetics; Basal ganglia; Biological Sciences; Cell Membrane - metabolism; Chorea; Corpus Striatum - cytology; Corpus Striatum - pathology; Cyclic AMP - metabolism; Disorders; Embryo, Mammalian; Ganglia; HEK293 Cells; Human motion; Humans; Huntington Disease - genetics; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Hydrolysis; Isoenzymes - genetics; Isoenzymes - metabolism; Molecular modelling; Movement disorders; Mutation; Neostriatum; Neurodegenerative diseases; Neurons - cytology; Neurons - enzymology; Patch-Clamp Techniques; Phenotypes; Phosphodiesterase; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Primary Cell Culture; Protein Domains - genetics; Proteolysis; Rats; Recombinant Proteins - genetics; Recombinant Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1916398117

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.