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.
journal_name
Proc Natl Acad Sci U S Aauthors
Tejeda GS,Whiteley EL,Deeb TZ,Bürli RW,Moss SJ,Sheridan E,Brandon NJ,Baillie GSdoi
10.1073/pnas.1916398117subject
Has Abstractpub_date
2020-01-07 00:00:00pages
677-688issue
1eissn
0027-8424issn
1091-6490pii
1916398117journal_volume
117pub_type
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