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Sci. Signal., 21 July 2009
Vol. 2, Issue 80, p. ra36
[DOI: 10.1126/scisignal.2000308]

RESEARCH ARTICLES

Inhibition of mTOR Signaling in Parkinson’s Disease Prevents L-DOPA–Induced Dyskinesia

Emanuela Santini1, Myriam Heiman2, Paul Greengard2, Emmanuel Valjent1,3,4,5, and Gilberto Fisone1,2*

1 Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
2 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.
3 INSERM, UMR-S839, 75005 Paris, France.
4 Université Pierre et Marie Curie, 75005 Paris, France.
5 Institut du Fer à Moulin, 75005 Paris, France.

Abstract: 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.

* To whom correspondence should be addressed. E-mail: gilberto.fisone{at}ki.se

Citation: E. Santini, M. Heiman, P. Greengard, E. Valjent, G. Fisone, Inhibition of mTOR Signaling in Parkinson’s Disease Prevents L-DOPA–Induced Dyskinesia. Sci. Signal. 2, ra36 (2009).

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