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.
Highlights
It is expected that the disease phenotypes are due to the aberrant function of the major striatal splice variant PDE10A2
As phenotypes underpinned by Phosphodiesterase 10A (PDE10A) mutations are caused by functional abnormality of the most abundant isoform, we generated plasmids containing PDE10A2-FLAG with the human GAF-A mutations Y107C and A116P and the GAF-B mutations F300L and F334L
The ability to hydrolyze cyclic adenosine monophosphate (cAMP) with increasing concentrations of the highly selective PDE10A inhibitor MP10 was similar between PDE10A2 WT, F300L, and F334L forms, confirming previous reports [15]
Summary
It is expected that the disease phenotypes are due to the aberrant function of the major striatal splice variant PDE10A2. PDE10A coordinates cAMP signaling in striatal medium spiny neurons, the main input region of the basal ganglia circuitry and the most vulnerable cells to degeneration during Huntington’s disease (HD) [1, 2]. 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 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
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