PMID- 19622833
OWN - NLM
STAT- MEDLINE
DCOM- 20090929
LR  - 20220318
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 2
IP  - 80
DP  - 2009 Jul 21
TI  - Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced 
      dyskinesia.
PG  - ra36
LID - 10.1126/scisignal.2000308 [doi]
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.
FAU - Santini, Emanuela
AU  - Santini E
AD  - Department of Neuroscience, Karolinska Institutet, Retzius vag 8, 171 77 
      Stockholm, Sweden.
FAU - Heiman, Myriam
AU  - Heiman M
FAU - Greengard, Paul
AU  - Greengard P
FAU - Valjent, Emmanuel
AU  - Valjent E
FAU - Fisone, Gilberto
AU  - Fisone G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20090721
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Antiparkinson Agents)
RN  - 0 (Carrier Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Receptors, Dopamine D1)
RN  - 0 (Transcription Factors)
RN  - 46627O600J (Levodopa)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antiparkinson Agents/*adverse effects/pharmacology
MH  - Carrier Proteins/*metabolism
MH  - Dyskinesia, Drug-Induced/etiology/*metabolism
MH  - Levodopa/*adverse effects/pharmacology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes
MH  - Parkinsonian Disorders/drug therapy/*metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - Proteins
MH  - Receptors, Dopamine D1/*metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/metabolism
EDAT- 2009/07/23 09:00
MHDA- 2009/09/30 06:00
CRDT- 2009/07/23 09:00
PHST- 2009/07/23 09:00 [entrez]
PHST- 2009/07/23 09:00 [pubmed]
PHST- 2009/09/30 06:00 [medline]
AID - 2/80/ra36 [pii]
AID - 10.1126/scisignal.2000308 [doi]
PST - epublish
SO  - Sci Signal. 2009 Jul 21;2(80):ra36. doi: 10.1126/scisignal.2000308.