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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...

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Autores principales: Tejeda, Gonzalo S., Whiteley, Ellanor L., Deeb, Tarek Z., Bürli, Roland W., Moss, Stephen J., Sheridan, Eamonn, Brandon, Nicholas J., Baillie, George S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
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.
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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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