title: p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism.
abstract: The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Schintu
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Alvarsson
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Roberta
authors.initials: R
authors.lastname: Marongiu
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 greengard@rockefeller.edu per.svenningsson@ki.se.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, 171 76 Stockholm, Sweden; greengard@rockefeller.edu per.svenningsson@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000502:physiology*; D020820:Dyskinesias / Q000503:physiopathology*; D007980:Levodopa / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D009418:S100 Proteins / Q000502:physiology*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D007980:Levodopa; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10
keywords: 6-hydroxydopamine; S100A10; dopamine; tacrine; tremor