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Phosphodiesterase 10A (PDE10A) belongs to a family of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate.1 PDE10A is highly enriched in striatal medium spiny neurons (MSNs), where it regulates intracellular signaling.1 PDE10A has been proposed as a therapeutic target for Huntington disease (HD), a disorder that preferentially affects MSNs, based on the observation that pharmacologic inhibition of PDE10A in transgenic HD mice significantly improved behavioral and neuropathologic abnormalities.2 However, earlier work had shown that striatal PDE10A levels in HD mice already decline to minimal levels before onset of motor symptoms,3 possibly because mutant huntingtin represses PDE10A transcription. Also, postmortem analysis of striatum of 3 patients with HD revealed strong reduction of PDE10A levels.3 Depletion of PDE10A in HD striatum would at first sight seem hard to reconcile with a beneficial effect of PDE10A inhibitors in HD. However, a recent study reported a dramatic increase, rather than decrease, of PDE10A protein in MSNs of HD mice.4 In light of these conflicting results and the strong interest in development of PDE10A inhibitors for clinical use in HD, it is important to determine whether PDE10A levels are affected in the striatum of patients with HD in vivo.
Acknowledgment:
The authors thank the study subjects for their participation. K.V.L. and W.V. are Senior Clinical Investigators of the Research Foundation—Flanders.
Footnotes
Supplemental data at www.neurology.org
Author contributions: R. Ahmad: acquisition, analysis and interpretation of data, statistical analysis, drafting the manuscript. S. Bourgeois: acquisition and analysis of data. A. Postnov: analysis of data. M. Schmidt: revising the manuscript for content. G. Bormans: revising the manuscript for content. K. Van Laere: study concept and design, acquisition and interpretation of data, study supervision, revising the manuscript for content. W. Vandenberghe: study concept and design, patient recruitment, acquisition and interpretation of data, revising the manuscript for content.
Disclosure: R. Ahmad, S. Bourgeois, and A. Postnov report no disclosures. M. Schmidt is an employee of Janssen Pharmaceutica NV, Beerse, Belgium. G. Bormans received financial support from Janssen Pharmaceutica for the development and preclinical evaluation of 18F-JNJ42259152. K. Van Laere and W. Vandenberghe report no disclosures. Go to Neurology.org for full disclosures.
Study funding: G. Bormans received financial support from Janssen Pharmaceutica for the development and preclinical evaluation of 18F-JNJ42259152.
- Received May 24, 2013.
- Accepted in final form September 12, 2013.
- © 2014 American Academy of Neurology
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