Parkinson’s drug steadies Rett breathing in mice

In a University of Connecticut experiment, mice missing one copy of MECP2 slipped into the same unnerving rhythm seen in Rett syndrome: apnea, gasping, hyperventilation, then apnea again. A Parkinson’s drug, pramipexole, helped bring their breathing back toward normal.

Rett syndrome is caused by a mutation or deletion of the MECP2 gene on the X chromosome and is most common in girls. The body regulates each breath through two sensors: one in the brainstem that detects carbon dioxide, and another around the carotid artery that detects oxygen. Monica Strain, a neurophysiologist at Boston Children’s Hospital at Harvard, tested both systems in mice. Pure oxygen stabilized breathing in the MECP2-deficient animals, while rising carbon dioxide changed it very little.

That result shifted attention to the neck. Strain worked with Sevolod Polotsky at George Washington University to deliver a gel containing a virus around the carotid body, blocking MECP2 in the oxygen-sensing cells without affecting the brain’s carbon dioxide sensors. The target is only two grains of sand in size in mice and sits where the carotid artery splits. Normal mice given the treatment began breathing like mice with Rett syndrome.

The next clue came from gene activity in the carotid bodies. Genes involved in dopamine expression were less active in the Rett mice. “Dopamine is inhibitory in the carotid body,” Dan Mulkey said, leaving the system “driving without brakes.” Strain and Eliandra da Silva then found that boosting dopamine signaling with pramipexole helped normalize the animals’ breathing.

Concretely, the work gives researchers a possible new route toward treating one of Rett syndrome’s most visible and frightening symptoms, using a medicine that already exists for another disease. It does not yet give families a proven treatment: the result comes from a mouse model, and the researchers describe pramipexole as a candidate to explore rather than an established Rett therapy.