Striatal Overexpression of ΔJunD Resets L-DOPA-Induced Dyskinesia in a Primate Model of Parkinson Disease

Background: Involuntary movements, or dyskinesia, represent a debilitating complication of dopamine replacement therapy for Parkinson disease (PD). The transcription factor Delta FosB 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 Delta FosB 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 Delta FosB protein and messenger RNA (mRNA) levels across two subpopulations of macaques with differential dyskinesia severity. Second, we tested the causal implication of Delta FosB in this primate model. Serotype 2 adeno-associated virus (AAV2) vectors were used to overexpress, within the motor striatum, either Delta FosB or Delta JunD, a truncated variant of JunD lacking a transactivation domain and therefore acting as a dominant negative inhibitor of Delta FosB. Results: A linear relationship was observed between endogenous striatal levels of Delta FosB and the severity of dyskinesia in Parkinsonian macaques treated with L-DOPA. Viral overexpression of Delta FosB did not alter dyskinesia severity in animals previously rendered dyskinetic, whereas the overexpression of Delta JunD, 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.