A case of (peripheral) nerves

Every day, Waisman Center researcher John Svaren deals with nerves – peripheral nerves, that is.

Peripheral nerves connect the brain and spinal cord to our limbs and organs, serving as vital communication relays that allow us to sense and respond to the world around us.

“These nerves are really interesting because they contain some of the longest cells in the body,” says Svaren, who is also a professor in the UW-Madison School of Veterinary Medicine. “You can have a cell that stretches all the way from the spinal cord to the big toe!” But with great length comes great vulnerability, and peripheral nerves are susceptible to damage from mechanical, chemical and genetic causes.

Partly to protect them from damage, and partly to expedite the transmission of nerve impulses, nerve cells are wrapped in a jelly-roll-like substance called the myelin sheath. When the myelin sheath around nerve cells is damaged or disrupted, it can lead to disorders such as multiple sclerosis and Charcot-Marie-Tooth disease (CMT).

Searching for a cure for Charcot-Marie-Tooth disease

CMT is one of the more common inherited diseases of the nervous system and affects one out of 2,500 individuals.

Symptoms of CMT can vary from person to person but weakness, decreased sensation and muscle loss in the legs and feet, difficulty in walking and maintaining balance, and frequent tripping and falling are commonly seen in affected individuals. As the disease progresses the symptoms may spread to the arms and hands.

There is currently no cure for CMT but Svaren’s lab is working to better understand the molecular machinations behind the disease. His lab focuses on the most common type of CMT, CMT1A, which is caused by a specific genetic mutation that impairs cells that manufacture and maintain the myelin sheath around peripheral nerves.

In individuals with CMT1A, these cells – called Schwann cells – have an extra copy of a gene called PMP22. This extra copy causes the cells to produce too much PMP22 protein and “is a great reason to study how cells regulate how much PMP22 is made,” says Svaren. “Then we can try and apply that knowledge to figure out a way to dial down PMP22 levels in Schwann cells and potentially develop a therapy for CMT1A.”

Recent research from the Svaren lab (you can read the papers here and here) has identified several proteins that play important roles in regulating myelin production in Schwann cells.

Svaren has also been collaborating with a consortium of researchers, laboratories, companies, and government agencies, such as the National Institutes of Health, to screen almost 2.5 million chemical compounds in the search for one that can lower how much PMP22 is made in Schwann cells.

“We are down to a hundred or so compounds that look promising,” says Svaren. “Obviously we are hoping to come up with a cure [for CMT1A] but we are also interested in learning if we can use these drugs to identify what regulates how much myelin is made by Schwan cells.”

Recovering from nerve injuries

Schwann cells also play important roles in how nerves respond to injury. “The peripheral nervous system is remarkably regenerative and there are now several lines of evidence that Schwann cells are vital for this process,” says Svaren.

In fact, research has shown that after an injury, Schwann cells can communicate with the immune system and attract specific immune cells that clear the area for the healing process, assist nerve cells to regenerate and even lay down ‘tracks’ for the recovering nerve cells to grow along.

“Schwann cells are remarkably plastic [i.e. they are able to switch between different roles], and we are trying to understand how they are reprogrammed after an injury to gain the capacity to do all these things,” says Svaren.

To explore how Schwann cells become masters-of-all-trades, Svaren uses techniques that take into account a cell’s entire genome. He studies how proteins called transcription factors regulate which genes get turned on or off in Schwann cells after an injury to peripheral nerves.

“We have collected a lot of data over the years and now we can start to explore – on a really detailed, molecular level – what happens in Schwann cells after a nerve injury,” says Svaren.

Combining laboratory and clinical research

Like many scientists, Svaren is driven by the desire to discover. “I am passionate about making connections where we didn’t know they existed and understanding what no else has yet understood,” he says.

Svaren is also happy to be able to combine laboratory experiments and more clinical and translational research. “At the Waisman Center, and the University of Wisconsin-Madison, along with a network of scientists dedicated to CMT research, I have the opportunity to interact with medical doctors and neurologists as well as researchers and scientists,” he says. “Through these interactions, I have come to realize and appreciate the clinical potential and relevance of my research.”

Svaren is also active in the CMT community. He serves on the board of directors of the Charcot-Marie-Tooth Association (CMTA), a not-for-profit organization whose mission – much like his own – is “to support the development of new drugs to treat CMT, to improve the quality of life for people with CMT, and, ultimately, to find a cure.”

By Adityarup “Rup” Chakravorty, Waisman Communications