Striatal overexpression of DeltaJunD resets L-DOPA-induced dyskinesia in a primate model of Parkinson disease

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) admi...

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Published in:Biological psychiatry (1969) Vol. 66; no. 6; p. 554
Main Authors: Berton, Olivier, Guigoni, Céline, Li, Qin, Bioulac, Bernard H, Aubert, Incarnation, Gross, Christian E, Dileone, Ralph J, Nestler, Eric J, Bezard, Erwan
Format: Journal Article
Language:English
Published: United States 15.09.2009
Subjects:
Analysis of Variance
Animals
Antiparkinson Agents - adverse effects
Benserazide - adverse effects
Corpus Striatum - diagnostic imaging
Corpus Striatum - metabolism
Disease Models, Animal
Dopamine Plasma Membrane Transport Proteins - metabolism
Drug Combinations
Dyskinesia, Drug-Induced - pathology
Dyskinesia, Drug-Induced - therapy
Female
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Gene Expression Regulation - physiology
Genetic Therapy - methods
Genetic Vectors - physiology
Green Fluorescent Proteins - genetics
Humans
Iodine Radioisotopes
Levodopa - adverse effects
Linear Models
Macaca fascicularis
Male
MPTP Poisoning - diagnostic imaging
MPTP Poisoning - drug therapy
MPTP Poisoning - pathology
Nortropanes
Protein Binding - drug effects
Proto-Oncogene Proteins c-jun - genetics
Proto-Oncogene Proteins c-jun - metabolism
Radionuclide Imaging
RNA, Messenger - metabolism
ISSN:1873-2402, 1873-2402
Online Access:Get full text
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Summary: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. 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. 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. 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.
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ISSN:1873-2402
1873-2402
DOI:10.1016/j.biopsych.2009.04.005