Innovative research paves way for more effective treatment for ALS and other neurodegenerative diseases
Late actor Christopher Reeve, best known for his role as Superman in the 1970s and '80s, became an activist for spinal cord injury research after being paralyzed in a horseback-riding accident-making him a lifelong wheelchair user and on a ventilator.
Reeve, who died in 2004, was among about 300,000 people nationally living with a spinal cord injury, with respiratory complications being the most common cause of illness and death, according to the Christopher & Dana Reeve Foundation, which he and his late wife created to support the research.
But the results of a new study, led by researchers at Case Western Reserve University's School of Medicine, show promise that a group of nerve cells in the brain and spinal cord-called interneurons-can boost breathing when the body faces certain physiological challenges, such as exercise and environmental conditions associated with altitude.
The researchers believe their discovery could lead to therapeutic treatments for patients with spinal cord injuries who struggle to breathe on their own. Their findings were recently published in the journal Cell Reports.
"While we know the brainstem sets the rhythm for breathing," said Polyxeni Philippidou, an associate professor in the Department of Neurosciences at Case Western Reserve University School of Medicine and lead researcher, "the exact pathways that increase respiratory motor neuron output, have been unclear-until now."
The research team included collaborators from the University of St. Andrews in the United Kingdom, the University of Calgary in Canada and the Biomedical Research Foundation Academy of Athens in Greece.
Legacy of spinal cord research at CWRU
The School of Medicine's Department of Neurosciences has been studying motor circuits and spinal cord injury for more than 30 years, beginning with the late Jerry Silver, a founding faculty member of the department who was recognized by the Reeve Foundation for his work.
Silver, who died in January, was a member of the Scientific Advisory Council of the Reeve Foundation and the Scientific Board of the International Spinal Research Trust in England. He was awarded the Christopher Reeve-Joan Irvine Research Medal for critical contributions to the promotion of repair of the damaged spinal cord; the Reeve Foundation also posted a tribute after his passing.
In addition, former department Chair Lynn Landmesser, who died in late 2024, was a pioneering neuroscientist and helped develop the Cleveland Brain Health Initiative at the School of Medicine. She made pivotal contributions to the study of motor circuit development and was a member of the National Academy of Sciences.
The study
By identifying a subset of interneurons as a new and potentially easy-to-reach point for treatment in spinal cord injuries and breathing-related diseases, the researchers believe doctors may be able to develop therapies to help improve breathing in people with such conditions.
The study showed that blocking signals from these spinal cord cells made it harder for the body to breathe properly when there was too much carbon dioxide (CO2) in the blood, a condition known as hypercapnia.
CO2 is created in the body when cells make energy. Red blood cells carry CO2 from organs and tissues to the lungs, where it is exhaled. If the body can't shed CO2, it can build up in the blood, making it hard to breathe and leading to respiratory failure.
"These spinal cord cells are important for helping the body adjust its breathing in response to changes like high CO2 levels," Philippidou said.
In this study, the team used genetically modified mouse models to explore the pathways involved in breathing. The researchers mapped neuron connections, measured neuron electrical activity, observed the models' behavior and used microscopy to visualize neuron structure and function-all focused on spinal cord nerve cells involved in breathing.
"We were able to define the genetic identity, activity patterns and role of a specialized subset of spinal cord neurons involved in controlling breathing," Philippidou said.
The team is now testing whether targeting these neurons in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, and Alzheimer's disease can help restore breathing.
