Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease.

Ahmed MR, Berthet A, Bychkov E, Porras G, Li Q, Bioulac BH, Carl YT, Bloch B, Kook S, Aubert I, Dovero S, Doudnikoff E, Gurevich VV, Gurevich EV, Bezard E
Sci Transl Med. 2010 2 (28): 28ra28

PMID: 20410529 · PMCID: PMC2933751 · DOI:10.1126/scitranslmed.3000664

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.

MeSH Terms (22)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Animals Antiparkinson Agents Behavior, Animal Dose-Response Relationship, Drug Dyskinesias Endocytosis G-Protein-Coupled Receptor Kinases Gene Knockdown Techniques Genetic Therapy Humans Lentivirus Levodopa Macaca Oxidopamine Parkinsonian Disorders Rats Rats, Sprague-Dawley Receptors, Dopamine D1 Receptors, Dopamine D2 Rotation Signal Transduction

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