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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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 1; pp. 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 Journal Article
LanguageEnglish
Published United States National Academy of Sciences 07.01.2020
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Online AccessGet full text
ISSN0027-8424
1091-6490
1091-6490
DOI10.1073/pnas.1916398117

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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.
AbstractList 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.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.
Phosphodiesterase 10A (PDE10A) is as a target of interest in Huntington’s disease (HD) as levels of the enzyme have been shown to decrease prior to the development of the hallmark motor symptoms. Clearly, a better understanding of how PDE10A protein levels change as HD develops is required. Here we show that mutations in the regulatory GAF domains of PDE10A that cause hyperkinetic syndromes in humans lead to misprocessing of the PDE10A enzyme that ultimately leads to targeted degradation by the ubiquitin proteasome system or clearance by autophagy. Both mechanisms result in a paucity of PDE10A activity that lead to a loss of movement coordination. Our research suggests that similar mechanisms may underpin PDE10A loss during HD. 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.
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.
Author Brandon, Nicholas J.
Whiteley, Ellanor L.
Sheridan, Eamonn
Baillie, George S.
Tejeda, Gonzalo S.
Deeb, Tarek Z.
Bürli, Roland W.
Moss, Stephen J.
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Copyright Copyright © 2020 the Author(s). Published by PNAS.
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Issue 1
Keywords cyclic AMP
Huntington’s disease
PDE10A
GAF domain
phosphodieaterase
Language English
License Copyright © 2020 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
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Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved November 20, 2019 (received for review October 15, 2019)
1Present address: Department of Neurology, University of California, San Francisco, CA, 94158.
2Present address: Jnana Therapeutics, Boston, MA 02210.
Author contributions: G.S.T., E.S., N.J.B., and G.S.B. conceived the study; G.S.T., E.L.W., T.Z.D., R.W.B., S.J.M., E.S., N.J.B., and G.S.B. designed research; G.S.T., E.L.W., T.Z.D., and R.W.B. performed experiments and analyzed data; G.S.T., N.J.B., and G.S.B. wrote the paper with input from all authors.
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Snippet A robust body of evidence supports the concept that phosphodiesterase 10A (PDE10A) activity in the basal ganglia orchestrates the control of coordinated...
Phosphodiesterase 10A (PDE10A) is as a target of interest in Huntington’s disease (HD) as levels of the enzyme have been shown to decrease prior to the...
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SubjectTerms 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
Title Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme
URI https://www.jstor.org/stable/26897509
https://www.ncbi.nlm.nih.gov/pubmed/31871190
https://www.proquest.com/docview/2335154873
https://www.proquest.com/docview/2330327393
https://pubmed.ncbi.nlm.nih.gov/PMC6955301
Volume 117
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