Background
Involuntary movements, or dyskinesia, represent a debilitating complication of dopamine
replacement therapy for Parkinson disease (PD). The transcription factor ΔFosB 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 ΔFosB
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 ΔFosB protein and messenger RNA (mRNA) levels across two
subpopulations of macaques with differential dyskinesia severity. Second, we tested
the causal implication of ΔFosB in this primate model. Serotype 2 adeno-associated
virus (AAV2) vectors were used to overexpress, within the motor striatum, either ΔFosB
or ΔJunD, a truncated variant of JunD lacking a transactivation domain and therefore
acting as a dominant negative inhibitor of ΔFosB.
Results
A linear relationship was observed between endogenous striatal levels of ΔFosB and
the severity of dyskinesia in Parkinsonian macaques treated with L-DOPA. Viral overexpression
of ΔFosB did not alter dyskinesia severity in animals previously rendered dyskinetic,
whereas the overexpression of ΔJunD 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.
Key Words
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Article info
Publication history
Published online: June 01, 2009
Accepted:
April 1,
2009
Received in revised form:
March 24,
2009
Received:
February 17,
2009
Identification
Copyright
© 2009 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
