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Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955301/ https://www.ncbi.nlm.nih.gov/pubmed/31871190 http://dx.doi.org/10.1073/pnas.1916398117 |
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author | Tejeda, Gonzalo S. Whiteley, Ellanor L. Deeb, Tarek Z. Bürli, Roland W. Moss, Stephen J. Sheridan, Eamonn Brandon, Nicholas J. Baillie, George S. |
author_facet | Tejeda, Gonzalo S. Whiteley, Ellanor L. Deeb, Tarek Z. Bürli, Roland W. Moss, Stephen J. Sheridan, Eamonn Brandon, Nicholas J. Baillie, George S. |
author_sort | Tejeda, Gonzalo S. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6955301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-69553012020-01-14 Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme Tejeda, Gonzalo S. Whiteley, Ellanor L. Deeb, Tarek Z. Bürli, Roland W. Moss, Stephen J. Sheridan, Eamonn Brandon, Nicholas J. Baillie, George S. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-01-07 2019-12-23 /pmc/articles/PMC6955301/ /pubmed/31871190 http://dx.doi.org/10.1073/pnas.1916398117 Text en Copyright © 2020 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Tejeda, Gonzalo S. Whiteley, Ellanor L. Deeb, Tarek Z. Bürli, Roland W. Moss, Stephen J. Sheridan, Eamonn Brandon, Nicholas J. Baillie, George S. Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme |
title | Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme |
title_full | Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme |
title_fullStr | Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme |
title_full_unstemmed | Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme |
title_short | Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme |
title_sort | chorea-related mutations in pde10a result in aberrant compartmentalization and functionality of the enzyme |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955301/ https://www.ncbi.nlm.nih.gov/pubmed/31871190 http://dx.doi.org/10.1073/pnas.1916398117 |
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