Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements.
Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor DeltaFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of DeltaFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of DeltaFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic DeltaFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of DeltaFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high DeltaFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal DeltaFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.
Cao
Xuebing
X
Department of Neurology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
Yasuda
Toru
T
Uthayathas
Subramaniam
S
Watts
Ray L
RL
Mouradian
M Maral
MM
Mochizuki
Hideki
H
Papa
Stella M
SM
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D020820:Dyskinesias / Q000145:classification / Q000209:etiology* / Q000378:metabolism*; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013565:Sympatholytics / Q000633:toxicity; D013997:Time Factors
C483819:Fosb protein, mouse; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D013565:Sympatholytics; C528955:junD protein, mouse; D049452:Green Fluorescent Proteins; D007980:Levodopa; D016627:Oxidopamine