Striatal overexpression of DeltaJunD resets L-DOPA-induced dyskinesia in a primate model of Parkinson disease.
Biological Psychiatry. 2009-09-01; 66(6): 554-561
Read on PubMed
1. Biol Psychiatry. 2009 Sep 15;66(6):554-61. doi: 10.1016/j.biopsych.2009.04.005.
Epub 2009 May 28.
Striatal overexpression of DeltaJunD resets L-DOPA-induced dyskinesia in a
primate model of Parkinson disease.
Berton O(1), Guigoni C, Li Q, Bioulac BH, Aubert I, Gross CE, Dileone RJ, Nestler
EJ, Bezard E.
(1)Department of Psychiatry, University of Pennsylvania Medical School,
Philadelphia, Pennsylvania 19104-3403, USA.
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
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.
PMID: 19481198 [Indexed for MEDLINE]