title: PET imaging shows loss of striatal PDE10A in patients with Huntington disease.
abstract: 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.
authors.affiliation: From University Hospitals Leuven (R.A., S.B., A.P., K.V.L., W.V.); KU Leuven (R.A., A.P., G.B., K.V.L., W.V.); and Janssen Pharmaceutica NV (M.E.S.), Beerse, Belgium.
authors.forename: Rawaha
authors.initials: R
authors.lastname: Ahmad
authors.forename: Sophie
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Andrey
authors.initials: A
authors.lastname: Postnov
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmidt
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: Wim
authors.initials: W
authors.lastname: Vandenberghe
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D049229:Dendritic Spines / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D013347:Subcellular Fractions / Q000473:pathology
chemical_list: C581925:2-((4-(1-(2-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)phenoxy)methyl)-3,5-dimethylpyridine; D011720:Pyrazoles; D011725:Pyridines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases