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Tuesday, April 20, 2021

UW researcher studies the rare Pelizaeus-Merzbacher disease

The enormity of research available at UW-Madison comes as no surprise to the students on campus. The research subjects range from common ones such as cancer research to something as rare as Pelizaeus-Merzbacher disease. Truth be told, my understanding of PMD was minimal prior to this article since this disease affects one in almost 200,000 males in the United States. (PMD is an X-linked recessive trait that is only present in males; females are only possible carriers of PMD)

Regardless, the research conducted by Dr. Ian Duncan, professor of Neurology at the School of Veterinary Medicine, is certainly captivating in its process of understanding the underlying mechanism of this neurodegenerative disease as well as finding potential therapeutic approaches.

There are three types of PMD: connatal, classical and spastic paraplegia type II, which is the mildest form among the three. Connatal is the most severe as death may occur at an early stage in life (around three weeks of birth), but patients with this form of PMD typically live until 10 years of age. The classical PMD patients, on the other hand, can live up to 50 years old but with serious cognitive and physical limitations.

Duncan’s research team is interested in the classical form of PMD and uses dogs as their models. “Rodent models are usually either connatal or mild forms of PMD,” said Duncan. This interest in dog studies allows for the opportunity to study the developmental process of PMD while creating a close representation to the human disease.

“We are investigating a point mutation in the canine model to analyze how it affects the development of myelin in the spinal cord and brain. The mutation is in the proteolipid protein-1 (PLP1) gene, which is the major protein of central nervous system myelin,” said Duncan who has spent 30 years on this research.

Symptoms of the disease, which include delayed intellectual function and motor abilities, are mostly common in both humans and dogs. Young males are diagnosed with PMD based on their neurologic symptoms and lab tests. Boys with PMD frequently have nystagmus, which is the flickering of the eyes, though this is not seen in affected dogs. Furthermore, the MRI scans of individuals with the disease confirm the absence of myelin in the brain.

The underlying pathological defect in PMD is in the myelin sheath, which is a fat layer that acts as an insulator to increase neuronal connectivity along nerve fibers known as axons. In individuals with PMD, axons either have no myelin or only a thin wrapping. The clinical severity of the disease reflects the severity of the lack of myelin, i.e. in connatal disease there is almost a complete absence of myelin whereas in spastic paraplegia type II most axons have thin sheaths.

Duncan’s study highlighted a fascinating quality of the disease. In the canine model, the myelination of the spinal cord gradually increases after birth; however, the brain remains poorly myelinated. “The long-term observation is that there is an accumulation of myelin despite the fact that the oligodendrocytes, which are myelin-producing cells, are genetically dysfunctional,” said Duncan. In fact, these cells not only retain their function, but are able to increase in number and produce more myelin in the spinal cord.

This finding further leads to the speculation that gene therapy, a conventional method of treating genetic disorders, may not be necessary. Instead, treatment may be possible by attempting to increase the production of oligodendrocytes during early development, especially in the brain.

Another important observation about the study is axon survival in the central nervous system. It is thought that when axons are either thinly myelinated or non-myelinated they will eventually die. Contrary to this belief, axons actually survive despite undergoing reactive changes. This is essential as myelinating these axons may indeed be the answer to treating PMD.

Currently, no treatment for PMD is present. Neurologists and clinicians usually provide supportive care to patients in hope of increasing one’s quality of life. However, the future may certainly be promising as Duncan’s next move in the study is to find therapeutic approaches in restoring myelin to the canine brain.

“We plan to use drugs to promote oligodendrocyte differentiation early in life to trigger early myelin formation,” said Duncan. It is hoped that trials conducted on dogs could possibly mirror future clinical practices to treat both canine patients and boys with PMD.

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The humorous and charismatic Duncan ended with some advice to students involved in science, “Be curious, ask the whys and stay curious.”

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