Ученые Университета Коннектикута выявили причину нарушений дыхания при синдроме Ретта и предложили лечение на основе препаратов от болезни Паркинсона

Hyperventilating. Breath holding until they turn blue. This abnormal breathing is frequent and disturbing in people with Rett syndrome, a rare genetic disease. Now University of Connecticut researchers report in the Sept. 1 issue of Current Biology why those episodes happen, and show how medications for an entirely different disease might help. Rett syndrome is a genetic disease caused by mutation or deletion of a single gene, MECP2, on the X chromosome. It’s most common in girls. People with Rett syndrome have intellectual disabilities and seizures, and frequently have limited use of their hands. Rett is not a degenerative disease—people who have it frequently live into adulthood—but the symptoms can be scary. Periods of apnea, or no breathing, can be followed by gasping and hyperventilating, and then apnea again, in an extreme cycle of bad breathing. “If you’re never watched your child’s body convulse until it needed chemicals to relax it, or watched as their lips turn blue and their skin a mottled grey, you’re more than lucky,” writes Megan Thorne, the mother of a girl with Rett syndrome, on her blog You Do You. One of the hallmarks of Rett syndrome are these episodes of disordered breathing. The body controls this fundamental function with two sensors. One is a group of cells in the brainstem that sense carbon dioxide levels in the blood. The other is a group of cells around the carotid artery in the neck, which sense oxygen levels. Both sensors are important to maintain healthy levels of those two gases in the bloodstream. Monica Strain ‘26 Ph.D., a neurophysiologist at Boston Children’s Hospital at Harvard, became interested in Rett syndrome when she was a graduate student in the lab of UConn neurophysiologist Dan Mulkey. Mulkey’s lab specializes in understanding how the brain controls breathing. Rett syndrome is considered a central nervous system disorder, meaning its core effects are in the brain. Past research at other labs had been inconclusive on exactly how the brain was involved in the breathing symptoms of Rett. Strain decided to focus her research on finding out. She used a mouse model of Rett syndrome that lacks a copy of the gene MECP2. The mice lacking MECP2 displayed the characteristic breath pattern of periodic apnea, gasping, and hyperventilating so well known to caregivers of people with Rett syndrome. Then, since Rett was known to be a central nervous system disease, she devised a way to disentangle the roles of the sensor in the brain and the sensor around the carotid artery: she would start each experiment with the mice breathing pure oxygen to ensure the peripheral chemoreceptors, those cells in the carotid artery in the neck, would be taken offline. Then, she would slowly increase the amount of carbon dioxide in the air, to study how the brain controls breathing on its own. But to Strain’s surprise, exposure to pure oxygen stabilized breathing in MECP2 deficient mice. It suggested that over-activation of peripheral chemoreceptors—the sensor cells around the carotid—drives the unstable breathing. Strain also found that the mice’s breathing didn’t change much in response to rising carbon dioxide levels.   Perhaps Rett was not just a central nervous system disorder. Strain thought maybe the peripheral chemoreceptors were involved after all.  To further test this, Strain needed to take normal mice and find a way to selectively delete the Rett syndrome gene, MECP2, just in the carotid body. This was extremely difficult. The carotid body in mice is tiny, the size of two grains of sand, and they sit in a delicate spot right where the carotid artery splits in two before it enters the brain. Strain reached out to Sevolod Polotsky at George Washington University, one of the few researchers in the world with experience using a virus to manipulate gene expression in the peripheral chemoreceptors.  Polotsky generously invited Strain to spend time in his lab to learn how to precisely inject a blob of gel so that it surrounded the carotid body but didn’t harm the artery. The gel contained a virus that blocked MECP2. When done on normal mice, blocked MECP2 only in the chemoreceptors that sensed oxygen. The carbon dioxide sensors in the brain were unaffected. And it worked—the mice began breathing like Rett syndrome mice, with the same episodes of hyperventilation and apnea.  Strain then analyzed all the gene expression in the carotid body of the Rett syndrome mice and contrasted them with normal mice. She found that genes that express dopamine were less active in the Rett syndrome mice.  “Dopamine is inhibitory in the carotid body,” says Mulkey. “So, in Rett, less dopamine means the loss of inhibition…so the system is driving without brakes,” Mulkey says. This may be the reason for unstable breathing in Rett syndrome. The super high oxygen levels in Strain’s initial experiment had acted like an override, slowing the peripheral chemoreceptors down. Rett syndrome is not the only disease that involves a lack of dopamine. Parkinson’s disease does as well, and a few drugs already exist for it. Strain, along with Eliandra da Silva, another researcher in the Mulkey lab, found that augmenting dopamine signaling with pramipexole, typically used to treat Parkinson’s disease, helped normalize breathing in MECP2 deficient mice.  “What’s exciting about this finding is the potential to build on treatments that already exist,” says Strain. “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.” This research was funded with grants from the National Institutes of Health: the National Heart, Lung, and Blood Institute, and the National Institute of Neurological Disorders and Stroke.