Striatal overexpression of DeltaJunD 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 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.
Berton
Olivier
O
Department of Psychiatry, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-3403, USA. bertonol@mail.med.upenn.edu
Guigoni
Céline
C
Li
Qin
Q
Bioulac
Bernard H
BH
Aubert
Incarnation
I
Gross
Christian E
CE
Dileone
Ralph J
RJ
Nestler
Eric J
EJ
Bezard
Erwan
E
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001545:Benserazide / Q000009:adverse effects*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004338:Drug Combinations; D004409:Dyskinesia, Drug-Induced / Q000473:pathology* / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000009:adverse effects*; D016014:Linear Models; D020267:MPTP Poisoning / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D009662:Nortropanes; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011877:Radionuclide Imaging
D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004338:Drug Combinations; D007457:Iodine Radioisotopes; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C005177:benserazide, levodopa drug combination; D049452:Green Fluorescent Proteins; D007980:Levodopa; D001545:Benserazide