Biological psychiatry · 2009
Striatal overexpression of DeltaJunD resets L-DOPA-induced dyskinesia in a primate model of Parkinson disease.
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Berton Olivier, Guigoni Céline, Li Qin, Bioulac Bernard H, Aubert Incarnation, Gross Christian E, Dileone Ralph J, Nestler Eric J, Bezard Erwan
Аннотация
BACKGROUND: Involuntary movements, or dyskinesia, represent a debilitating complication of dopamine replacement therapy for Parkinson disease (PD). The transcription factor DeltaFosB accumulates in the denervated striatum and dimerizes primarily with JunD upon repeated L-3,4-dihydroxyphenylalanine (L-DOPA) administration. Previous studies in rodents have shown that striatal DeltaFosB levels accurately predict dyskinesia severity and indicate that this transcription factor may play a causal role in the dyskinesia sensitization process.
METHODS: We asked whether the correlation previously established in rodents extends to the best nonhuman primate model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. We used western blotting and quantitative polymerase chain reaction (PCR) to compare DeltaFosB protein and messenger RNA (mRNA) levels across two subpopulations of macaques with differential dyskinesia severity. Second, we tested the causal implication of DeltaFosB in this primate model. Serotype 2 adeno-associated virus (AAV2) vectors were used to overexpress, within the motor striatum, either DeltaFosB or DeltaJunD, a truncated variant of JunD lacking a transactivation domain and therefore acting as a dominant negative inhibitor of DeltaFosB.
RESULTS: A linear relationship was observed between endogenous striatal levels of DeltaFosB and the severity of dyskinesia in Parkinsonian macaques treated with L-DOPA. Viral overexpression of DeltaFosB did not alter dyskinesia severity in animals previously rendered dyskinetic, whereas the overexpression of DeltaJunD dramatically dropped the severity of this side effect of L-DOPA without altering the antiparkinsonian activity of the treatment.
CONCLUSIONS: These results establish a mechanism of dyskinesia induction and maintenance by L-DOPA and validate a strategy, with strong translational potential, to deprime the L-DOPA-treated brain.
METHODS: We asked whether the correlation previously established in rodents extends to the best nonhuman primate model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. We used western blotting and quantitative polymerase chain reaction (PCR) to compare DeltaFosB protein and messenger RNA (mRNA) levels across two subpopulations of macaques with differential dyskinesia severity. Second, we tested the causal implication of DeltaFosB in this primate model. Serotype 2 adeno-associated virus (AAV2) vectors were used to overexpress, within the motor striatum, either DeltaFosB or DeltaJunD, a truncated variant of JunD lacking a transactivation domain and therefore acting as a dominant negative inhibitor of DeltaFosB.
RESULTS: A linear relationship was observed between endogenous striatal levels of DeltaFosB and the severity of dyskinesia in Parkinsonian macaques treated with L-DOPA. Viral overexpression of DeltaFosB did not alter dyskinesia severity in animals previously rendered dyskinetic, whereas the overexpression of DeltaJunD dramatically dropped the severity of this side effect of L-DOPA without altering the antiparkinsonian activity of the treatment.
CONCLUSIONS: These results establish a mechanism of dyskinesia induction and maintenance by L-DOPA and validate a strategy, with strong translational potential, to deprime the L-DOPA-treated brain.
Предметные рубрики MeSH
Analysis of VarianceAnimalsAntiparkinson AgentsBenserazideCorpus StriatumDisease Models, AnimalDopamine Plasma Membrane Transport ProteinsDrug CombinationsDyskinesia, Drug-InducedFemaleGene Expression RegulationGenetic TherapyGenetic VectorsGreen Fluorescent ProteinsHumansIodine RadioisotopesLevodopaLinear ModelsMPTP PoisoningMacaca fascicularisMaleNortropanesProtein BindingProto-Oncogene Proteins c-junRNA, MessengerRadionuclide Imaging