Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme
Open Access
- 23 December 2019
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (1), 677-688
- https://doi.org/10.1073/pnas.1916398117
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.This publication has 70 references indexed in Scilit:
- Characterization of Conformational Changes and Protein-Protein Interactions of Rod Photoreceptor Phosphodiesterase (PDE6)Online Journal of Public Health Informatics, 2012
- Regulated protein aggregation: stress granules and neurodegenerationMolecular Neurodegeneration, 2012
- DHHC5 Protein Palmitoylates Flotillin-2 and Is Rapidly Degraded on Induction of Neuronal Differentiation in Cultured CellsOnline Journal of Public Health Informatics, 2012
- Analysis of proteome dynamics in the mouse brainProceedings of the National Academy of Sciences of the United States of America, 2010
- Differential vulnerability of neurons in Huntington’s disease: the role of cell type‐specific featuresJournal of Neurochemistry, 2010
- Early endosomes and endosomal coatomer are required for autophagyThe Journal of cell biology, 2009
- A Role for NBR1 in Autophagosomal Degradation of Ubiquitinated SubstratesMolecular Cell, 2009
- Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal deathNature, 2004
- Protein aggregation and neurodegenerative diseaseNature Medicine, 2004
- Folding proteins in fatal waysNature, 2003