Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia.
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.
Santini
Emanuela
E
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
Heiman
Myriam
M
Greengard
Paul
P
Valjent
Emmanuel
E
Fisone
Gilberto
G
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011506:Proteins; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism
D000978:Antiparkinson Agents; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D017447:Receptors, Dopamine D1; D014157:Transcription Factors; D007980:Levodopa; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases