Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson’s disease.
Science Translational Medicine. 2010-04-21; 2(28): 28ra28-28ra28
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1. Sci Transl Med. 2010 Apr 21;2(28):28ra28. doi: 10.1126/scitranslmed.3000664.
Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in
experimental Parkinson’s disease.
Ahmed MR(1), 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.
(1)Department of Pharmacology, Vanderbilt University, 2200 Pierce Avenue, PRB422,
Nashville, TN 37232, USA.
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.
PMID: 20410529 [Indexed for MEDLINE]