Rethinking Parkinson’s Disease: M4 receptors (warning: nerdy stuff ahead)

The cardinal movement symptoms, stiffness, and tremor in Parkinson’s disease are caused by the gradual loss of neurons producing dopamine in a deep seated part of the brain called the substantia nigra.

Dopamine is essential for coordinating movement, and its loss disrupts the striatum, another deep brain region responsible for motor control.

This disruption leads to an imbalance between two key pathways: one that promotes movement and another that suppresses it, favoring suppression of movement.

The depletion of dopamine increases levels of another important chemical messenger in the brain, acetylcholine. Acetylcholine has complex effects in the striatum, acting on receptors to influence the motor circuits.

Among these receptors, the M4 muscarinic receptors stand out for their role in balancing the dopamine and the acetylcholine signals. These receptors are primarily found on pro-movement neurons, helping to fine-tune their activity.

It has been proposed that when dopamine is lost, the resulting increase in acetylcholine elevates M4 signaling, leading to suppression of movement and thereby worsening motor symptoms in Parkinson's.

In the current conventional theories, the combined changes in dopamine/acetylcholine levels are believed to underpin the movement difficulties seen in Parkinson’s disease.

Super-short summary: In parkinson disease, dopamine levels fall, and acetylcholine levels increase. Acetylcholine attaches to the M4 receptor. With increased levels of acetylcholine, we expect increased signal from the M4 receptors in Parkinson's.

The Study
Recent experiments have provided surprising insights. Researchers found that instead of becoming more active as expected, the acetylcholine-driven M4 receptor signal weakened after dopamine depletion.

This decrease in activity was due to down-regulated (fewer) receptors and, therefore, reduced signaling to pro-movement neurons - even with higher levels of acetylcholine.

Moreover, this weakened signaling appeared to interact with dopamine replacement therapy, such as levodopa, which is the standard treatment for the disease. Levodopa is often hampered over time by involuntary movements known as dyskinesias, adding another layer of complexity to the treatment of the disease as it progresses.

The study showed, unexpectedly, that restoring M4 transmission improved motor coordination and balance while also reducing involuntary movements caused by dopamine replacement therapy.

That's good news!

The study underlines the importance of M4 receptors in regulating motor circuits and opens up new possibilities for targeting these pathways in treatment.

Understanding these mechanisms could lead to more effective therapies for Parkinson’s disease and the complications that arise from its current treatments.

About the scientific paper:

First author: Beatriz E. Nielsen, USA
Published: Science Advances, November 2024
Link to paper: https://www.science.org/doi/10.1126/sciadv.adp6301