Houston, Texas, USA : Nerve cells stripped of their insulation can no longer carry vital information, leading to the numbness, weakness and vision problems often associated with multiple sclerosis. A new study shows an overlooked source may be able to replace that lost insulation and provide a new way to treat diseases like MS.
Cells called neurons make the central nervous system work by passing electrical signals along threadlike connections called axons. Axons do their work best when wrapped in an insulating coating of a fatty substance called myelin.
“When you lose myelin, axons don’t conduct at their normal speed or don’t conduct at all,” says Ian Duncan, a neuroscientist at the University of Wisconsin–Madison’s School of Veterinary Medicine. “And if enough of them are affected—such as in a big area of demyelination in MS—you develop clinical symptoms related to that part of the nervous system.”
Myelin is made by oligodendrocytes, cells that can reach out to several nearby axons to wrap parts of them in the protective myelin sheath.
Consensus has held that once an axon is robbed of its myelin, the only way to bring it back is by starting with fresh oligodendrocytes. Only oligodendrocytes arising from precursors called oligodendrocyte progenitor cells can apply a new coat of myelin to axons, goes the dogma. Thus, MS treatments aimed at remyelination have focused on recruiting progenitor cells in demyelinated areas (called plaques), and spurring them to develop.
However, researchers led by Duncan have shown in a study published today in the Proceedings of the National Academy of Sciences that starting from progenitor cells is not the only route to remyelination. In cats and rhesus macaques experiencing a severe loss of myelin, Duncan found fully developed oligodendrocytes already in place were reaching out and beginning to coat affected axons with myelin once again.
The catch, if there is one, is that to be helpful and remyelinate damaged axons, the adult oligodendrocytes may still need to have connections to surviving myelin segments—called “internodes”—on other axons.
“If this cell is still biologically active and maintaining these internodes, it can re-extend processes out to these demyelinated segments,” says Duncan, whose work is supported by the National Multiple Sclerosis Society. “Those processes can make new myelin sheaths, which end up being thinner and shorter than the previous internodes.”
But even thinner myelin will restore nerve function, as Duncan and colleagues reported in 2009.
Cats fed irradiated food for several months develop severe myelin loss throughout the nervous system. When the cats returned to a regular diet, nerve function was restored because of extensive myelin repair.
The cats’ demyelination problems are unusual as a lab model of the disease.
“The de facto model to study demyelination and remyelination is in a mouse fed a toxin called cuprizone,” Duncan says. “But the toxin kills oligodendrocytes. So, studying the mouse, you naturally wouldn’t see any of the original oligodendrocytes beginning remyelination.”
In the new study, the researchers looked at the cats’ nervous tissue and found a unique myelin mosaic—axons surrounded by thick layers of myelin (formed during development when the axons themselves grew) were interspersed with other axons surrounded by thin layers of myelin.
“The most likely explanation of that mosaic appearance is surviving oligos,” Duncan says. “Thick myelin sheaths are never seen following remyelination, just thin sheaths. And surviving adult oligodendrocytes are adjacent to these sites of demyelination, making them likely candidates for myelin repair.”
Sure enough, the researchers found oligodendrocytes connected to both thick and thin myelin sheaths in the cat spinal cord.
They also found this association when they reached back to a decades-old monkey model of demyelination. Neuroscientist Dimitri Agamanolis tried to make a model of another human demyelinating disease—called sub-acute combined degeneration and caused by Vitamin B12 deficiency—at Case Western Reserve University in the 1970s. Agamanolis had saved preserved blocks of sampled nervous tissue from the monkeys, and he shared them with Duncan. The monkeys’ myelin lesions resembled those in the cats.
“You see in the monkeys, too, single oligodendrocytes connected to mature myelin sheaths that also have processes extended out to and surrounding demyelinated axons,” Duncan says.
The UW–Madison researchers enlisted Grahame Kidd and the private research lab Renovo Neural in Cleveland to reconstruct stacks of electron microscope images of cat nerve cells into 3-D representations that show oligodendrocytes reaching up and down the spinal cord, sustaining mature myelin and remyelinating damaged sheaths.
The process may not be playing out in human MS patients fast enough to help mitigate the progression of the disease, Duncan says. Or too many oligodendrocytes may lose so many of their internodal connections that they become inactive or die.
But the discovery of the mature myelin-producing cells’ capacity for repair opens new opportunities to slow or reverse the disease.
“Right now, the emphasis is on promoting the numbers of oligo progenitors and their differentiation, particularly into adult oligodendrocytes,” says Duncan. “What this work provides is a different target.”
That target will call for new therapeutic approaches—finding drugs, for example, that rally the oligodendrocytes to reach out with new lifelines to damaged myelin sheaths.
“In fighting complex diseases, such as MS, the more tools you have on hand, the better,” Duncan says. “If these adult cells are recruitable in some fashion, we should be looking at ways to do it.”
Citation : Ian D. Duncan el al., “The adult oligodendrocyte can participate in remyelination,” PNAS. doi/10.1073/pnas.1808064115
A second study found that a little myelin goes a long way to restore nervous system function.
A Little Myelin Goes A Long Way To Restore Nervous System Function
In the central nervous system of humans and all other mammals, a vital insulating sheath composed of lipids and proteins around nerve fibers helps speed the electrical signals or nerve impulses that direct our bodies to walk, talk, breathe, swallow or perform any routine physical act.
But diseases of the nervous system, including multiple sclerosis (MS) in people, degrade this essential insulation known as myelin, disrupting the flow of information between the brain and the body, impairing movement, dimming vision and blunting the ability to function normally.
And while scientists have long studied myelin and understand its role in disease when it degrades, they have puzzled over how myelin repairs itself naturally and whether the thinned sheaths that are a hallmark of the healing nervous system are adequate for restoring the brain’s circuitry over the long haul.
This week (Oct. 23, 2017), in a study published in the Proceedings of the National Academy of Sciences, a team of researchers from the University of Wisconsin-Madison reports that in long-lived animals, renewed but thin myelin sheaths are enough to restore the impaired nervous system and can do so for years after the onset of disease.
The team’s findings reinforce the idea that thin myelin sheaths are a valid, persistent marker of remyelination, a hypothesis challenged by other recent research. “As the only biomarker of myelin repair available this would leave us without any means of identifying or quantifying myelin repair,” explains Ian Duncan, an expert on demyelinating diseases at the UW-Madison School of Veterinary Medicine and the senior author of the new study.
Duncan and his team looked at a unique genetic disorder that naturally afflicts Weimaraners, a breed of dog that as 12- to 14-day-old pups develop a severe tremor and loss of coordination. The condition is known to occur as the development of the myelin sheath in parts of the dog’s central nervous system is delayed. The symptoms gradually diminish and in most cases disappear altogether by 3-4 months of age.
“This is a very widespread mutation in the breed,” says Duncan, noting that myelin repair mimicking what is seen in remyelination is known to occur in these dogs as the rejuvenated nerve fibers have a thinned myelin sheath.
The new Wisconsin study was made possible as 13 years ago two Weimaraner pups, littermates, were seen as patients at the School of Veterinary Medicine and Duncan was able to maintain contact with the owners after the dogs were adopted and retrieve samples of spinal tissue after the dogs lived out their lives. As they aged, the dogs exhibited few signs of tremor and were deemed ‘neurologically normal’ up to 13 years of age.
The purpose of the study, says Duncan, was to confirm that thin myelin sheaths persisted and supported normal neurologic function.
To expand on the results, Duncan also looked at a condition in cats, another long-lived species that has been shown to fully recover nervous system function after demyelination. In particular, Duncan’s team was interested in remyelination of the optic nerves.
That element of the study, looking at remyelination two years after the onset of the condition, Duncan notes, is an example of “true demyelination and remyelination. We found that nearly every optic nerve fiber was remyelinated with a thin myelin sheath, which is important for understanding human disease because in multiple sclerosis, the optic nerve is often the first to be demyelinated.”
The new findings confirm that the gold standard for evaluating remyelination is the long-term persistence of thin myelin sheaths, which support nerve fiber function and survival, Duncan notes. The results are important for diseases like MS as it means that new therapies designed to promote myelin repair can be safely evaluated and quantified based on the presence of thin myelin sheaths.
Citation for second study: Ian D. Duncan el al., “Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function,” PNAS. doi/10.1073/pnas.1714183114