Tejeda, G. S. , Whiteley, E. L., Deeb, T. Z., Bürli, R. W., Moss, S. J., Sheridan, E., Brandon, N. J. and Baillie, G. S. (2020) Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme. Proceedings of the National Academy of Sciences of the United States of America, 117(1), pp. 677-688. (doi: 10.1073/pnas.1916398117) (PMID:31871190) (PMCID:PMC6955301)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Baillie, Professor George and WHITELEY, Ellanor and Tejeda, Dr Gonzalo |
| Authors: | Tejeda, G. S., Whiteley, E. L., Deeb, T. Z., Bürli, R. W., Moss, S. J., Sheridan, E., Brandon, N. J., and Baillie, G. S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| ISSN (Online): | 1091-6490 |
| Published Online: | 23 December 2019 |
| Copyright Holders: | Copyright © 2020 the Author(s) |
| First Published: | First published in Proceedings of the National Academy of Sciences of the United States of America 117(1):677-688 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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