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p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism.

Titlep11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism.
Publication TypeJournal Article
Year of Publication2016
AuthorsSchintu N, Zhang X, Alvarsson A, Marongiu R, Kaplitt MG, Greengard P, Svenningsson P
JournalProc Natl Acad Sci U S A
Date Published2016 Feb 02
KeywordsAnimals, Annexin A2, Dyskinesias, Levodopa, Mice, Mice, Knockout, Parkinsonian Disorders, S100 Proteins

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.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID26787846
PubMed Central IDPMC4747690