Degraded Synapses in the Retina Can Predict the Severity of MS

The disabling effects of multiple sclerosis may be caused in part by damaged connections between neurons, and this can be seen in the eye, UC San Francisco researchers have found.

They showed that degraded synapses in the retina, a thin layer of nerve tissue at the back of the eye, announce the beginning of severe MS symptoms, although they are far away from the brain and spinal cord where MS damage occurs.

The researchers also found a protein in the blood to detect this synaptic damage. This could be helpful in predicting progression to severe disease and assessing experimental treatments.

In MS the immune system attacks the myelin sheath that coats neurons to speed the transmission of nerve signals. The resulting damage causes tingling, numbness, weakness, and loss of coordination.

To see how the disease progresses, the UCSF team looked in the retina, the only place that neurons are visible in the body. And in both mice and humans with MS, they found a significant loss of synapses, which are the connections between neurons.

“It was a very surprising result, because these synapses are upstream of the demyelinating injury,” said Ari Green, MD, Chief of the Division of Neuroimmunology and Glial Biology and the Debbie and Andy Rachleff Distinguished Professor of Neurology. “This discovery told us that there’s something else going on.”

The study was published in Cell Reports.

Early detection could prevent damage

People with MS may feel fine much of the time in the early stages of their disease, although they must contend with occasional relapses. As some patients age, however, the relapses get longer and more frequent and eventually become overwhelming.

Current treatments can prevent relapses, but they may be given too late to protect the nerve cells, because by the time patients are diagnosed, the myelin has already been damaged.

Green, who specializes in treating patients with inflammatory diseases of the central nervous system and oversees the Innovation Program for Remyelination and Repair with co-senior author Jonah Chan, PhD, wanted to understand better how the disease progresses.

Looking at the retinas of mice with a form of MS, the team found that one layer, made up mostly of synapses, was thinner than normal, even though the mice didn’t yet have signs of severe disease.

Soon after the researchers saw these changes occur, the disease began a relentless progression.

The team also looked at blood from participants in a 2017 trial, called ReBUILD, in which Green and Chan had demonstrated the success of a remyelination drug they developed.

They found the patients’ blood contained a protein, called SNAP-25, that is released when synapses break down.

Green and Chan then looked at more than 800 MS patients who had been followed at UCSF for nearly 20 years and found that patients whose retinas were thinner than usual developed debilitating symptoms within a year.

It was a whole new way of looking at the disease.

“The breakdown of synapses isn’t something we’ve looked at in MS before,” Green said. “These damaged synapses could be a major contributor to the neurological problems MS patients contend with.”

A blood test for an earlier diagnosis

A blood test for SNAP-25 or a similar protein would let physicians see severe stages of the disease coming and enable them to intervene earlier.

That same protein also could be helpful in clinical trials of treatments for progressing MS to assess how well an experimental therapy is working.

Green is currently using SNAP-25 and other proteins as biomarkers in three trials of remyelinating drugs his team developed.

“We’re still marshalling evidence, but it appears that stopping demyelination will protect synapses and neurological function,” he said. “And that is our Holy Grail.”

Authors: Other authors include Christian Cordano, Sebastian Werneberg, Ahmed Abdelhak, Daniel Bennett, Alexandra Beaudry-Richard, Frederike Oertel, John Boscardin, Nora Jabassini, Lauren Merritt, Sonia Nocera, Jung Sin, Isaac Samana, Shivany Condor Montes, Kirtana Ananth, Antje Bischof, UCSF MS EPIC Team, Stephen Hauser, and Bruce A.C. Cree.

Funding: This work was supported by NIH grant R01NS105741, the Italian Multiple Sclerosis Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.