RT Journal Article SR Electronic T1 Inhibition of mTOR Signaling in Parkinson’s Disease Prevents l-DOPA–Induced Dyskinesia JF Science Signaling JO Sci. Signal. FD American Association for the Advancement of Science SP ra36 OP ra36 DO 10.1126/scisignal.2000308 VO 2 IS 80 A1 Santini, Emanuela A1 Heiman, Myriam A1 Greengard, Paul A1 Valjent, Emmanuel A1 Fisone, Gilberto YR 2009 UL http://stke.sciencemag.org/content/2/80/ra36.abstract AB Parkinson’s disease (PD), a disorder caused by degeneration of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by motor side effects, or dyskinesia. We show that administration of l-DOPA in a mouse model of Parkinsonism led to dopamine D1 receptor–mediated activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is implicated in several forms of synaptic plasticity. This response occurred selectively in the GABAergic medium spiny neurons that project directly from the striatum to the output structures of the basal ganglia. The l-DOPA–mediated activation of mTORC1 persisted in mice that developed dyskinesia. Moreover, the mTORC1 inhibitor rapamycin prevented the development of dyskinesia without affecting the therapeutic efficacy of l-DOPA. Thus, the mTORC1 signaling cascade represents a promising target for the design of anti-Parkinsonian therapies.