AAN 2025 | Beyond dopamine: exploring GPR6 as a therapeutic target in Parkinson’s disease

Parkinson’s disease for many, many decades really focused on dopamine, on dopamine repletion. Because of the severe depletion of dopamine in Parkinson’s disease beginning from the earliest stages, they really underlie a lot of the motor and functional symptoms of the disease. We’re also aware, though, that there is a lot more than dopamine that’s affected in Parkinson’s disease, perhaps even decades before. Other neurochemicals, other targets, dysfunction in serotonin and acetylcholine and norepinephrine, and these underlie autonomic and neuropsychiatric and enteric and other non-motor symptoms as well. So as our understanding of the widespread degeneration that occurs in Parkinson’s disease increases, we look for other targets to try to help motor symptoms and non-motor symptoms. Especially if we help motor symptoms, we don’t want to worsen non-motor symptoms. We like to help both with a novel target. We know for motor symptoms that the outflow pathways from the striatum, the direct and the indirect pathways, these sort of act as a brake and accelerate it to sort of balance outflow movement in a sense to have normal mobility, are disturbed in Parkinson’s disease due to the dopamine depletion. Initially, this gives rise to hypoactivity in the D1 direct or accelerated pathway. But there’s also increased activity in the breaking D2 indirect pathway. And this combination leads to hypomobility, too little movement, hypokinesia. So we try to restore that by giving back dopamine. Dopamine agonists, levodopa, that becomes dopamine. But there’s other ways of trying to target these pathways because there’s other proteins and other receptors that can be looked at. So we’ve really sought other non-dopaminergic ways over the past decade or more, looking at other molecules that might interact and help rebalance the direct or indirect pathway. GPR6 is a novel receptor that’s on the indirect pathway, and it modulates the outflow of the indirect pathway. It sits on the membrane of the medium spiny neuron, a medium spiny neuron that has these the two receptors that identify them as the origin of the indirect or breaking pathway. And by inhibiting this particular receptor we’re able to reduce some of the overactivity in that breaking pathway sort of releasing the break. So if we think about giving levodopa that’s like pressing on the accelerator in a car When we give medication to inhibit the GPR6 receptor, like solengepras, that’s like taking your foot off the brake. And sometimes you may get into a car and the emergency brake is on. You don’t realize it and you put it into gear and you press on the gas and it doesn’t quite go as well as we want to. And if we remove the brake, as inhibiting GPR6 can do, we can get better mobility. So the strategy of trying to identify novel targets has identified GPR6 as another mechanism that will allow us to remove some of the overactivity in the indirect pathway, in essence, removing that break and allowing a better balance and better movement in Parkinson’s disease.

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