Although supersensitivity of D 2 receptors is expected when parkinsonism is first apparent, the first L-dopa dose administered does not generally induce dyskinesia, but dyskinesia develops gradually over time.7 Accordingly, the D 2 /D 3 receptor agonists exert an antiparkinsonian effect with a reduced propensity to elicit dyskinesia when administered de novo in PD patients. 8 There is some evidence that D 1 messenger RNA (mRNA) levels are increased after dopaminergic treatment of the DA-depleted striatum in animal models of LID 9 ; that downstream signal transduction cascades is abnormal in LID, 10,11 including increased phosphorylation of cAMP-regulated phosphoprotein of 32kDa 12 ; and that an altered subcellular localization of D 1 receptors is involved in LID. 13 Moreover, a DA D 1 receptor agonist with proven antiparkinsonian action 14 induced LID similar to that induced by L-dopa in PD patients, 15 further suggesting that D 1 supersensitivity plays a key role in LID occurrence. Together, these observations call for a reassessment of the changes affecting D 1 and D 2 DA receptors in LID.In this study, taking advantage of a nonhuman primate (NHP) brain bank constituted to study the pathophysiology of LID, 16 we determined changes affecting D 1 and D 2 DA receptors within the striatum of four experimental groups: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa that shows overt dyskinesia. We show that LIDs are linked to a modification of both D 1 receptor expression and sensitivity of the D 1 -signaling cascade, reinforcing the hypothesis of the pivFrom the
Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the anti-parkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease. † To whom correspondence should be addressed. Eugenia.Gurevich@vanderbilt.edu (E.V.G.); Erwan.bezard@u-bordeaux2.fr (E.B.). * These authors contributed equally to this work.Author contributions: E. Bezard and E.V.G. designed and organized the experiments; E.V.G., V.V.G., M.R.A., Y.T.C., and S.K. designed, cloned, and produced viral vectors and viruses; E.V.G., M.R.A., Y.T.C., E. Bychkov, S.K., A.B., and G.P. performed rat behavioral, neurochemical, and histological experiments; E. Bezard, A.B., G.P., Q.L., B.H.B., B.B., I.A., S.D., and E.D. performed monkey behavioral, neurochemical, and histological experiments; E. Bezard and E.V.G. analyzed the data; E. Bezard, V.V.G., and E.V.G. wrote the paper. Competing interests:The authors have declared no competing interests. SUPPLEMENTARY MATERIAL www.sciencetranslationalmedicine.org/cgi/content/full/2/28/28ra28/DC1 Materials and Methods Fig. S1. The GFP-tagged GRK6 is functional and has the subcellular localization of the endogenous GRK6. Fig. S2. Antibodies to GRK6 selectively recognize GRK6A or GRK6B splicing variants. Fig. S3. The lentivirus carrying two chained miRNAs targets both GRK6A and GRK6B splice variants. Fig. S4. Infection of the rat striatum with the miRNA lentivirus induces the GRK6 knockdown. References NIH Public Access
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