Scientists at the Hunter James Kelly Research Institute (HJKRI) conduct research to better understand myelin, the fatty insulator that enables communication between nerve cells. The institute is named for the late son of Buffalo Bills quarterback Jim Kelly, who died in 2005 at age 8 from Krabbe leukodystrophy. The findings could lead to therapies to prevent or treat neurodegenerative diseases like MS.
About HJKRI
Scientists at HJKRI, named for the family of Buffalo Bills hall-of-fame quarterback Jim Kelly after his infant son Hunter died from Krabbe leukodystrophy, conduct research focused on better understanding myelin, a fatty insulator that enables communication between nerve cells. The scientists study myelin disorders, such as multiple sclerosis and Krabbe disease, and how they may be repaired. Keit Men Wong, PhD, a former HJKRI postdoctoral researcher who did the work with Beirowski and Babetto, is also a co-author of the paper.
Krabbe Leukodystrophy
Krabbe disease, also known as globoid cell leukodystrophy (GLD) and galactocerebrosidase deficiency, is a rare, inherited, fatal disorder that damages the white matter in the central and peripheral nervous systems. It is caused by a shortage (deficiency) of the enzyme galactosylceramidase, which normally breaks down fats in small containers called lysosomes within cells. Without this enzyme, these fats build up and destroy myelin, a fatty sheath that encases and protects nerve cells, so they can communicate with each other efficiently. The disorder is also characterized by the presence of abnormal cells in the brain and spinal cord that have multiple nuclei, or are larger than normal cells, called globoid cells.
Babies with Krabbe disease usually die at two to five years of age, regardless of treatment. However, bone marrow transplant can halt the progression of the disease in 30% of infants who receive a transplant before symptoms begin. The procedure is highly risky, so researchers are pursuing other ways to prevent or treat the disease.
The genetic mutation that causes Krabbe disease changes the instructions in a gene called GALC, which provides the instructions for making an enzyme called galactocerebrosidase. This enzyme helps break down certain fats in the body, including a substance called psychosine. Without enough galactosylceramide or other fats to break down, psychosine accumulates in the nervous system and causes myelin to be destroyed.
Research shows that a person who inherits a changed copy of the GALC gene from each parent has a 25 percent chance per pregnancy of developing Krabbe disease. Newborn screening programs in some states and countries test all babies for the condition shortly after birth. Newborn screening can identify affected babies and allow for HSCT before symptoms appear.
Vite’s team has developed an experimental therapy for the condition, which uses viral vectors to deliver a therapeutic genome directly into the central nervous system. The therapy restores function to the nerves and reduces psychosine levels. It has shown promise in animal models of the disease and in a patient with the juvenile form of the disorder. Vite’s team is now working to improve the therapy and make it more effective in humans.
Myelination
Scientists at HJKRI have found that a key process by which nerve cells build and repair the myelin sheath is controlled by neuronal activity. Their results suggest that the ability of the brain to adapt and respond to neuronal activity may also contribute to myelin plasticity and recovery in a manner that is more complex than previously thought.
A new study reveals that the fatty myelin sheath that wraps around nerve cell axons in the central nervous system speeds transmission of electrical signals to and from other brain cells. In multiple sclerosis (MS) and other demyelinating disorders, this process is disrupted, causing vision loss, weakness and numbness. The new research, published Jan. 22 in Science, centers on a type of brain cell called an oligodendrocyte. These cells produce myelin, the insulating coating that wraps around nerve cell axons.
The scientists have discovered that electrical signals passing through a nerve cell trigger the cell to release the chemical glutamate, which then activates another brain cell called an oligodendrocyte. The oligodendrocyte then begins producing myelin protein, which it wraps around the axon like electrical tape would around bare wires. This process, known as myelination, is crucial to brain function. In MS and other demyelinating diseases, the oligodendrocytes don’t produce enough myelin.
Previous research has shown that axonal myelination is dependent on the frequency and duration of the action potentials in a nerve cell. The new findings, however, suggest that the oligodendrocytes actually regulate this myelination by modifying the number and length of myelin sheaths on axons in an activity-dependent manner.
One way the oligodendrocytes do this is by changing the composition of the myelin sheath to increase its density and speed of conduction. The oligodendrocytes also promote the maturation of myelin sheaths by increasing their thickness. In addition, the oligodendrocytes modify the length of nodes where myelin sheaths meet, which may be important for the rapid propagation of fast-spiking neurons.
The study also suggests that astrocytes, which surround neurons and support the myelin sheath, also play a role in regulating myelination. Astrocytes release the lipids needed to fuel myelin production, promote the survival of oligodendrocyte precursor cells and provide K+ buffering during neuronal activity. Using mouse models, the researchers showed that when astrocytes were removed from the brain, there was a reduction in oligodendrocyte proliferation and myelin production. Conversely, when astrocytes were added back to the brain, there was an increased number of oligodendrocytes and myelin in the cortex and cerebellum.
Neurodegenerative Diseases
UB neurobiologists have long studied the cells that form our nervous system and how they communicate with each other to coordinate movement, speech, thinking, and the hundreds of other vital functions our bodies perform. These neurons, or nerve cells, are known as axons, and their fragile, finger-like projections (also called dendrites) can carry critical signals throughout the body. Axons, however, are among the first casualties in certain neurological diseases, resulting in debilitating symptoms such as muscle weakness or numbness of limbs. A new study led by UB scientists published in Nature Neuroscience this week reveals that Schwann cells, which surround axons within nerves like a glove covers a hand, can come to the rescue of injured axons.
Schwann cells, which are named for the son of a former Buffalo Bills quarterback, are the primary providers of myelin sheaths that wrap around axons and facilitate their smooth transmission of signals. The UB study shows that these cells can sense when axons are sick, and by regulating the breakdown of glucose to produce two molecules of pyruvate, a simpler sugar, they can release sugars to support the axons. By pharmacologically and genetically manipulating this metabolic pathway, the researchers were able to protect axons from various injuries in mice.
The research also reveals that Schwann cells can sense the presence of toxic protein clumps, such as beta-amyloid, found in Alzheimer’s disease. Scientists have long believed that blocking the clumping of these proteins will help stave off dementia. But the recent findings suggest that axons may be harmed long before beta-amyloid accumulates in the brain.
The UB findings, which were supported by two grants from the Muscular Dystrophy Association awarded to Beirowski and co-author Shermali Gunawardena, could be of broad relevance to other neurodegenerative conditions involving myelin. “Our discovery paves the way for therapies that target both Schwann cells and myelin sheaths to prevent or treat the symptoms of Krabbe and other leukodystrophies, as well as multiple sclerosis and hereditary peripheral neuropathies,” Beirowski said. The UB team’s work builds on earlier discoveries by colleagues at the University of Texas Health Science Center, who were the first to show that Schwann cell protective proteins can be triggered by myelin sheath injury.