The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.

G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D(2) dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA.

Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease.

Neurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.