Bench to Bedside | February/March 2017

Oligodendrocytes Yield New Insights for Myelin Repair in Multiple Sclerosis

Cells with a funny name called oligodendrocytes make myelin in your central nervous system, which includes your brain, spinal cord, and optic nerves. “Oligo” means “small.” “Dendros” are “branches” that come out of a cell. And “cytes” are “cells.” So oligodendrocytes are very small cells with many lacey arms. The lab of Judith Grinspan, PhD, research professor of Neurology at Children’s Hospital of Philadelphia and the Pereleman School of Medicine at the University of Pennsylvania, has a particular expertise in starting oligodendrocytes as precursor cells in a lab dish and observing their maturation to better understand the myelin-making process. Her study team’s observations are yielding clues on how to encourage myelin to regenerate in people who have multiple sclerosis.

Oligodendrocytes’ arms, also known as processes, produce the myelin sheath, which is a membrane rich in lipids, or fat, that coats our nerves and allows for conduction of nervous impulses. Myelin functions like the insulation on an electrical wire. If the insulation is not intact, the electricity does not get where it needs to go. So, if part of your myelin sheath is missing, the messages sent by nerves in your brain — telling your big toe to wiggle, for example — don’t reach your muscles.

Myelin is destroyed in multiple sclerosis, and depending on which areas of the brain have demyelination, patients may experience various symptoms, such as movement problems, vision loss, and fatigue. About 450,000 people in U.S. and Canada are living with multiple sclerosis, and studies suggest that 2 to 5 percent have a history of symptom onset before age 18.

While the cause of multiple sclerosis remains unknown, it is considered to be an autoimmune disease, in which the immune system recognizes the central nervous system as foreign and attacks the myelin. Researchers have helped to identify drug therapies for multiple sclerosis that target the immune system; however, little progress has been made on finding factors at the cellular level that could improve myelin repair.

“Researchers like me who work on myelination want to know everything about how these oligodendrocytes tick and how they make myelin,” Dr. Grinspan said.

In a paper published in January by the Journal of Neurochemistry, Dr. Grinspan and her colleagues reported on a novel insight they gained about this process, albeit in a serendipitous way. They were working with Kelly Jordan-Sciutto, PhD, chair and professor of Pathology at Penn’s School of Dental Medicine, on a study looking at the effect of the antiretroviral drugs that are used to treat HIV on oligodendrocytes and myelin. The study team noted that one of the drugs dysregulated a protein called sterol regulatory element binding protein (SREBP), which is thought to control the synthesis of fat all over the body. SREBP raised the investigators’ curiosity even higher when they realized that no one had ever studied it in oligodendrocytes.

Hubert Monnerie, PhD, a post-doc in the department of Neurology who at the time was working with Dr. Grinspan, performed a series of lab experiments that proved SREBP indeed was present on the oligodendrocytes, and levels of SREBP increased as the cells matured. Next, he explored SREBP’s role in the cells by using a chemical to block the SREBP. When SREBP was inhibited, the oligodendrocytes did not form new myelin.

“What we saw was really a remarkable phenomenon,” Dr. Grinspan said. “When we inhibited our favorite protein, SREBP, there were no processes. They were gone. It’s as if the cells curled them up instead of extending them. We saw it all over the dish. And then we wanted to see if this was reversible, and sure enough, if we washed out the blocking agent, the processes were back.”

The investigators performed more preliminary experiments, with the assistance of John Millar, PhD, director of the Metabolic Tracer Resource at Penn, that suggest SREBP controls the synthesis of cholesterol in oligodendrocytes that is necessary for the cells to make a proper myelin sheath. This is an important finding, not just because it provides new insights about how oligodendrocytes form myelin. Dr. Grinspan pointed out that on the therapeutic side, one idea being discussed in the multiple sclerosis field is the use of a class of drugs called statins because they have anti-inflammatory properties; however, statins also lower cholesterol, which could perhaps hinder lipid synthesis in oligodendrocytes and myelin regeneration.

Future research is needed to better understand exactly how SREBP may act as a lipid control factor in oligodendrocytes and if the protein has other fundamental effects on the cells’ development. With the help of a grant from the National Multiple Sclerosis Society, Dr. Grinspan is working to establish an animal model in which SREBP is inactivated in oligodendrocytes. This may reveal novel ways to create conditions in the brain that are beneficial for myelin repair and ease symptoms of multiple sclerosis.

“We’ll learn more about all the factors that you need to have in one place to promote myelination,” Dr. Grinspan said. “I am extremely grateful to the Multiple Sclerosis Society for their support.”


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Produced by The Children’s Hospital of Philadelphia Research Institute.

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