Parkinson’s drug shows potential for Rett breathing problems in mice
Study links breathing instability to carotid body dysfunction
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A medication that’s currently used to treat Parkinson’s disease showed potential for addressing breathing problems associated with Rett syndrome in a mouse study.
Scientists found that abnormal activity in the carotid body, a small structure in the neck that helps monitor oxygen levels in the blood, contributed to Rett-like breathing problems in mice. Specifically, the data pointed to diminished dopamine signaling in the carotid body as a possible cause of its increased activity.
Parkinson’s is marked by low dopamine levels, and several Parkinson’s treatments work by boosting dopamine levels or mimicking dopamine’s activity. The researchers found that one such therapy, pramipexole (sold as Mirapex ER and generics), reduced abnormally high breathing activity and briefly stabilized breathing after a period of low oxygen in a mouse model of Rett syndrome.
Parkinson’s drug offers a possible new approach
“What’s exciting about this finding is the potential to build on treatments that already exist,” Monica Strain, PhD, first author of the study and a former graduate student in the lab of University of Connecticut neurophysiologist Dan Mulkey, said in a university news story.
“Our work provides a foundation for exploring whether drugs developed to target dopamine signaling in Parkinson’s disease could be repurposed for Rett syndrome. We hope this work can ultimately help expand treatment options for people living with Rett,” Strain added.
The study, “Carotid body dysfunction contributes to respiratory instability in Rett syndrome,” was published in Current Biology.
Rett syndrome is a genetic disorder chiefly caused by mutations in the MECP2 gene, which can reduce the amount of functional MeCP2 protein. Rett mainly affects the central nervous system (the brain and spinal cord), resulting in developmental and behavioral abnormalities.
Breathing issues are common among people with Rett syndrome. Patients may experience episodes of apnea, or stopped breathing, followed by gasping and hyperventilation. These episodes can be distressing for patients and their loved ones and, in some cases, can be life-threatening.
There are two main sensors that help the body regulate breathing: a group of cells in the brainstem that helps monitor carbon dioxide levels in the blood, and the carotid body, a structure in the neck that helps monitor oxygen levels.
Because Rett syndrome is primarily considered a central nervous system disorder, researchers initially focused on whether Rett-related breathing problems might be caused by problems with the brain’s carbon dioxide-sensing system. To better understand the role of this system, they had Rett-model mice breathe pure oxygen, which suppresses activity from the carotid body so the brain’s carbon dioxide response can be studied in relative isolation.
Carotid body emerges as key driver of breathing instability
The researchers had originally planned to slowly increase levels of carbon dioxide so they could study how the brain sensor’s activity changed. But they found that the mice’s breathing changed little as carbon dioxide levels rose — and when the mice were breathing pure oxygen, they stopped displaying Rett-like breathing patterns. The fact that these breathing abnormalities went away when activity from the carotid body was suppressed suggested that this sensor outside the brain was contributing to the breathing problems.
Building on this finding, the researchers conducted experiments in otherwise healthy male mice in which they selectively reduced MeCP2 levels in cells of the carotid body. Reducing MeCP2 in this specific sensor was sufficient to produce key Rett-like breathing abnormalities, the researchers found.
Further analyses indicated that reduced MeCP2 in the carotid body was linked with changes in the expression of genes involved in dopamine signaling, consistent with diminished dopamine signaling.
“Dopamine is inhibitory in the carotid body. So, in Rett, less dopamine means the loss of inhibition…so the system is driving without brakes,” said Dan Mulkey, PhD, senior study author at the University of Connecticut.
The researchers then tested the impact of treatment with pramipexole, which is a dopamine receptor agonist (a molecule that mimics dopamine), in male mice with a model of Rett syndrome. The treatment reduced abnormally high breathing activity and briefly stabilized breathing after a period of low oxygen, supporting the possibility that Parkinson’s treatments targeting dopamine signaling could be explored for Rett-related breathing issues.
“These results identify the peripheral chemoreceptors [in the carotid body] as high-priority therapeutic targets for disordered breathing in [Rett syndrome],” the researchers concluded.
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