Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme
| Autor: | Eamonn Sheridan, Ellanor L. Whiteley, Tarek Z. Deeb, Roland Bürli, Nicholas J. Brandon, Gonzalo S. Tejeda, George S. Baillie, Stephen J. Moss |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Movement disorders
Patch-Clamp Techniques Mutant GAF domain Primary Cell Culture Biology Huntington's disease Protein Domains medicine Autophagy Cyclic AMP Animals Humans Gene Phenocopy Neurons Multidisciplinary PDE10A Phosphoric Diester Hydrolases Hydrolysis Cell Membrane Chorea Compartmentalization (psychology) Biological Sciences medicine.disease Embryo Mammalian Phenotype Corpus Striatum Recombinant Proteins Cell biology Rats Isoenzymes HEK293 Cells Huntington Disease Mutation Proteolysis medicine.symptom Neuroscience Huntington’s disease phosphodieaterase |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance 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. |
| Databáze: | OpenAIRE |
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