Research ArticleParkinson’s Disease

Lentiviral Overexpression of GRK6 Alleviates l-Dopa–Induced Dyskinesia in Experimental Parkinson’s Disease

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Science Translational Medicine  21 Apr 2010:
Vol. 2, Issue 28, pp. 28ra28
DOI: 10.1126/scitranslmed.3000664

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Treatment for Tremors Without Side Effects

As neurodegenerative diseases go, Parkinson’s disease is fairly treatable. Oral doses of l-dopa can still the tremors and normalize a patient’s movements—for a time. Eventually, however, most patients develop involuntary aimless gestures call dyskinesias, thought to be a result of oversensitive dopamine responses in the brain, caused by years of taking l-dopa. Now, Bezard and his colleagues have taken aim at a regulator of the dopamine receptor, G protein–coupled receptor kinase 6 (GRK6), to combat these disturbing side effects.

The dopamine receptor, like others in its family, will desensitize after use. In this state, the receptor can no longer be activated and is taken up by the cell. The first step in desensitization is the phosphorylation of the receptor by GRK6. After many years of l-dopa, the amount of GRK in the brain starts to decline and the machinery that desensitizes the receptor does not work properly, leading, it is believed, to the uncontrolled movements of dyskinesia. The authors reinstated GRKs with gene therapy in mice that had an induced parkinsonian syndrome and showed that the dyskinesia-like movements of the mice were much reduced and, as expected, desensitization of the dopamine receptor was normalized. Repeating this experiment in macaque monkeys, in which a Parkinson-like disease had been artificially induced by a toxic agent, gave similar results: Increasing GRK6 expression in the brain could markedly improve the dyskinesia-like side effects of long-term l-dopa treatment, likely by correcting the desensitization of dopamine receptors. Notably, correction of GRK6 did not interfere with the therapeutic effects of l-dopa—an important attribute for the eventual application of such a therapy.

These authors have identified a signaling pathway that seems to be responsible for the worst side effect of the standard treatment for Parkinson’s disease. Manipulation of one of its members, GRK6, or other components of dopamine receptor sensitization may prove to be an effective treatment for these side effects without hindering the efficacy of one of the most useful drugs in the neurologist’s armamentarium.

Footnotes

  • * These authors contributed equally to this work.

  • Citation: M. R. Ahmed, A. Berthet, E. Bychkov, G. Porras, Q. Li, B. H. Bioulac, Y. T. Carl, B. Bloch, S. Kook, I. Aubert, S. Dovero, E. Doudnikoff, V. V. Gurevich, E. V. Gurevich, E. Bezard, Lentiviral Overexpression of GRK6 Alleviates l-Dopa–Induced Dyskinesia in Experimental Parkinson's Disease Sci. Transl. Med. 2, 28ra28 (2010).

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