Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease.
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 antiparkinsonian 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.
Ahmed
Mohamed R
MR
Department of Pharmacology, Vanderbilt University, 2200 Pierce Avenue, PRB422, Nashville, TN 37232, USA.
Berthet
Amandine
A
Bychkov
Evgeny
E
Porras
Gregory
G
Li
Qin
Q
Bioulac
Bernard H
BH
Carl
Yonatan T
YT
Bloch
Bertrand
B
Kook
Seunghyi
S
Aubert
Incarnation
I
Dovero
Sandra
S
Doudnikoff
Evelyne
E
Gurevich
Vsevolod V
VV
Gurevich
Eugenia V
EV
Bezard
Erwan
E
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020820:Dyskinesias / Q000150:complications* / Q000517:prevention & control*; D004705:Endocytosis / Q000187:drug effects; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics / Q000627:therapeutic use*; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D007980:Levodopa; D008251:Macaca; D016627:Oxidopamine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D012399:Rotation; D015398:Signal Transduction / Q000187:drug effects
D000978:Antiparkinson Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6
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