Natural experiment, dogged investigation, yield clue to devastating neurological disease

April 20, 2017 by David Tenenbaum, University of Wisconsin-Madison
Natural experiment, dogged investigation, yield clue to devastating neurological disease
A normal 9-month-old rat has myelin (blue) throughout the brain but the age-matched mutant rat (below) appears to have none. (Scale bar is 1 mm; front of brain is at right.). Credit: DUNCAN LAB, UW–MADISON, WITH PERMISSION FROM ANNALS OF NEUROLOGY

After a 29-year quest, Ian Duncan, a professor of veterinary medicine at the University of Wisconsin–Madison, has finally pinpointed the cause of a serious neurologic disease in a colony of rats.

His new study, now online in the journal Annals of Neurology, is more than the conclusion of a personal and intellectual odyssey, however. Duncan has just shown that the rat abnormality closely resembles a rare human mutation that results in severe neurologic dysfunction. The human disease can affect many parts of the brain and has been called H-ABC.

Indeed, both conditions arise from mutations in the same gene.

Crucially, both abnormalities affect the production and maintenance of —the white, fatty insulation that nerves need to carry electrical signals. The deterioration of myelin in the brain causes the common neurologic disorder multiple sclerosis. Myelin defects are also at the root of the leukodystrophies—genetic disorders that include H-ABC.

Duncan's examination of nervous system tissue from both conditions revealed a telltale overgrowth of tiny tubes known as microtubules in oligodendrocytes, the cells that make myelin and deposit it on nerve fibers.

The Annals study offers a window on a rare disease—and also on the broader issue of myelin formation. "For a , we have provided a model that did not exist before," Duncan says, "and we've shown that it's based on microtubule accumulation in oligodendrocytes. Now we've seen similar changes in the and the human cells."

The roots of the new publication include a chance observation by two Chilean scientists, a couple of eyebrow-raising trips across the U.S. border, and the drive and persistence that have fashioned Duncan into a long-distance skier and competitive triathlete.

In 1988, Duncan learned that Bjorn and Ruth Holmgren, who had fled the Pinochet regime in Chile and settled in Mexico, had isolated rats with "an interesting tremor" at their laboratory in Puebla. Through a chain of colleagues, they identified Duncan for his interest in disorders of myelin, and offered him some nervous system tissue.

The handoff went down at a neuroscience meeting in Toronto, Duncan says. "I was standing by my poster when I detected the strong smell of fixative (chemicals used to preserve biological samples). A leaking bag containing rat brain and spinal cord samples was given to me by a Mexican scientist. While returning to Madison, the U.S. customs agent wanted to know what I was carrying. I said, 'It's fixed brain tissue, it's non-infective,' and he let me through."

Natural experiment, dogged investigation, yield clue to devastating neurological disease
In the mutant spinal cord, the oligodendrocyte, a cell that makes myelin, is surrounded by conductive fibers (called axons, marked with *) that lack myelin sheaths. On higher magnification, this cell has a huge increase in microtubules (arrows) that fill the cytoplasm and line up with cell membranes. Credit: BENJAMIN AUGUST

Later, when Duncan decided to breed the rats in Madison, he visited Puebla. On his return, "I was waved through the O'Hare airport customs with a cageful of rats—and no questions asked. That was before 9/11."

As Duncan's lab studied the rats, they observed the rampant growth of microtubules, and identified the general location of the gene responsible. But they could not identify it precisely.

Microtubules are structures in a cell's internal skeleton that supply both mechanical stiffness and a "railroad track" to transport molecules within the cell. The system goes haywire when the cell gets clogged with microtubules that block normal transport, Duncan says. "Microtubules accumulate with time, and they are everywhere in the cell and along all the processes that grow out from it. This affects the transport of myelin basic protein, which is a major constituent of myelin."

On a separate track, Marjo van der Knaap, a world-renowned pediatric neurologist at VU University Medical Center in Amsterdam, was studying a new syndrome in children, and named it H-ABC for its effect on myelin and certain nerve cells. In 2012 and 2013, van der Knaap and others identified a mutation in the TUBB4A gene, which makes a protein for microtubules.

In early 2016, Duncan learned about van der Knaap's work from John Svaren, a fellow professor of at UW–Madison. "I read the study and thought, 'This has to be what the rat has,'" Duncan says. "Originally, we thought this was a rat disease with no apparent human counterpart."

Svaren also searched databases on rat genes and noted that the Tubb4A gene was exactly where Duncan and his colleague Fang-Yuan Li had previously predicted. Shortly thereafter they identified a mutation in the rat Tubb4A gene.

Finally, in May 2016, Duncan and van der Knaap went over their findings. "She had postmortem tissue from a patient who had succumbed to the disease, and under the electron microscope, I saw the same microtubule abnormality in human oligodendrocytes as we described in the rats. That was critical."

The new rat model could become a testing ground for medicines that inhibit microtubule formation, Duncan says. It could also support insights into the larger group of leukodystrophies, genetic disorders with a wide range of causes and symptoms.

And, Duncan says, an improved understanding of how oligodendrocytes form and maintain myelin, and how those essential processes go awry, "could open a new window of understanding on the more widespread myelin diseases."

Explore further: Rare neurological disease shines light on health of essential nerve cells

More information: Ian D. Duncan et al. A mutation in thegene leads to microtubule accumulation with hypomyelination and demyelination, Annals of Neurology (2017). DOI: 10.1002/ana.24930

Related Stories

Rare neurological disease shines light on health of essential nerve cells

January 22, 2015
Ian Duncan is a Scotsman with the iron discipline and stamina of a competitive marathoner, triathlete and cross-country skier. As a neuroscientist at the School of Veterinary Medicine at the University of Wisconsin-Madison, ...

Finding challenges accepted view of MS: Unexpectedly, damaged nerve fibers survive

February 6, 2013
(Medical Xpress)—Multiple sclerosis, a brain disease that affects over 400,000 Americans, causes movement difficulties and many neurologic symptoms. MS has two key elements: The nerves that direct muscular movement lose ...

MicroRNA treatment restores nerve insulation, limb function in mice with multiple sclerosis

March 27, 2017
Scientists partially re-insulated ravaged nerves in mouse models of multiple sclerosis (MS) and restored limb mobility by treating the animals with a small non-coding RNA called a microRNA.

Stem cells help explain varied genetics behind rare neurologic disease

March 30, 2017
Researchers at Case Western Reserve University School of Medicine have successfully grown stem cells from children with a devastating neurological disease to help explain how different genetic backgrounds can cause common ...

Recommended for you

Neuroscientists suggest a model for how we gain volitional control of what we hold in our minds

January 16, 2018
Working memory is a sort of "mental sketchpad" that allows you to accomplish everyday tasks such as calling in your hungry family's takeout order and finding the bathroom you were just told "will be the third door on the ...

New study reveals why some people are more creative than others

January 16, 2018
Creativity is often defined as the ability to come up with new and useful ideas. Like intelligence, it can be considered a trait that everyone – not just creative "geniuses" like Picasso and Steve Jobs – possesses in ...

Even without nudging blood pressure up, high-salt diet hobbles the brain

January 16, 2018
A high-salt diet may spell trouble for the brain—and for mental performance—even if it doesn't push blood pressure into dangerous territory, new research has found.

Brain imaging predicts language learning in deaf children

January 15, 2018
In a new international collaborative study between The Chinese University of Hong Kong and Ann & Robert H. Lurie Children's Hospital of Chicago, researchers created a machine learning algorithm that uses brain scans to predict ...

Preterm babies may suffer setbacks in auditory brain development, speech

January 15, 2018
Preterm babies born early in the third trimester of pregnancy are likely to experience delays in the development of the auditory cortex, a brain region essential to hearing and understanding sound, a new study reveals. Such ...

BOLD view of white matter

January 15, 2018
The brain consists of gray matter, which contains the nerve cell bodies (neurons), and white matter, bundles of long nerve fibers (axons) that until recently were considered passive transmitters of signals between different ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.