GRKs in Parkinson’s Disease

Parkinson’s disease (PD) is a common age-related neurodegenerative disorder caused by selective degeneration of dopaminergic neurons in the substantia nigra and subsequent loss of dopamine (DA) in the striatum, the brain region essential for the control of movement. People with PD suffer from motor deficits that include bradykinesia (slowness of movement) or akinesia (absence of movement). Five DA receptor subtypes belonging to the GPCR superfamily mediate the action of DA in the striatum. When DA is lost, the signaling via DA receptors is severely modified, leading to supersensitive behavioral and molecular responses to dopaminergic stimulation.  Use of L-DOPA, a DA precursor, in a attempt to restore the DA level in the striatum, remains the most effective way to manage PD symptoms. However, L-DOPA therapy leads to various motor complications, including dyskinesia (abnormal involuntary movements), in a large proportion of PD patients. Since L-DOPA-induced dyskinesia (LID) is severely debilitating to PD patients, this is a very active area of research. LID is also a fascinating example of neural plasticity gone wrong. However, the molecular mechanisms of LID remain obscure.

Since aberrations in the dopaminergic signaling appear to be the prime cause of motor deficits in PD as well as L-DOPA-induced motor complications, the GPCR desensitization system specifically designed to control the GPCR signaling may play a critical role in the events unleashed by the DA depletion and subsequent treatment with dopaminergic drugs. We have found that loss of DA in the rodent model of PD causes a reduction in the expression of GRK isoforms, likely leading to excessive dopaminergic signaling.  Recently, we have demonstrated, in collaboration with Dr. Erwan Bezard (University of Bordeaux, France), that lentivirus-mediated overexpression of GRK6 in the striatum ameliorates LID and improves the therapeutic action of L-DOPA in rodent and primate models of PD. GRK6 overexpression in the dopamine-depleted striatum normalizes signaling pathways and reduces accumulation of the transcription factor deltaFosB, a known marker of dyskinesia.

Our data established GRK6 as a novel therapeutic target for PD. However, much more remains to be done before we fully understand the role of GRKs in the regulation of dopaminergic signaling in PD and LID. We are interested in the role of other GRK isoforms in these conditions. We also want to know which signaling mechanisms mediate the effect of GRK6 on LID. Finally, we may be able to create more potent GRK proteins to improve L-DOPA therapy in PD or to find another way to target GRKs for therapy.