Researchers Study Novel Proteins’ Role in Myelination

The novel molecules, called prohibitins, are required for nerves to form correctly and remain healthy. 

Feltri and fellow researchers identified the prohibitins in 2014 using a newly discovered way to study the interface where cells in the myelination process connect. “To identify them, we used a innovative cell chamber assay to isolate the proteins that are located in the cellular part of Schwann cells that are used to contact neurons,” she explains. 

Prohibitins are conserved transmembrane proteins found in mitochondria, plasma membranes and nuclei. They function as signaling adaptors and chaperones, and they are involved in adhesion, signaling and senescence. 

“Prohibitins are required for normal Schwann cell development and to maintain a healthy myelin sheath and healthy axons,” says Feltri, who is a faculty member in the genetics, genomics and bioinformatics program and a member of the Hunter James Kelly Research Institute (HJKRI).

Schwann cells produce myelin — the fatty substance that protects axons and is required for conduction of nerve impulses — and Feltri’s lab observed that deletion of prohibitins in Schwann cells in mice causes dysmyelination, demyelination and axonal degeneration.

Impaired formation or destruction of myelin causes diseases such as Guillain-Barre syndrome and Charcot-Marie-Tooth disease. Diseases of peripheral myelin are among the most common neuromuscular disorders and cause significant disability. 

The mechanisms that underlie how peripheral myelin-forming Schwann cells differentiate and myelinate, how they maintain a healthy myelin sheath and how they support axons are only partially understood.

Feltri is using a combination of state-of-the art techniques in vivo and in vitro to test the hypotheses that prohibitin-2 in Schwann cells is part of a plasma membrane signaling complex that interact with axons early in development, while a prohibitin-1/prohibitin-2 complex in the mitochondria maintains myelin and axon integrity. 

She and members of her lab are attempting to identify prohibitins interactors and discover how prohibitins regulate senescence, proteostasis and mitochondria function in Schwann cells. 

These data are likely to define the novel function of prohibitins in myelination and axon protection, and they may reveal new molecular mechanisms that are important for axo-glial interactions during peripheral neuropathies.

The overarching goal of Feltri’s lab is to translate basic findings into a cure for demyelinating diseases.

In a 2016 study, published in Nature Neuroscience, Feltri and her colleagues found that Schwann cells respond to mechanical stimuli by activating certain molecules that are then transferred to the nucleus. This triggers the formation of myelin, the protective coating that neurons need to function.

In 2014 she was awarded a $1.7 million grant to explore the role of integrins and Rho GTPases in cellular communication processes that lead to myelination in peripheral nerves. She and her team are assessing why the myelination process fails when these proteins are defective. They plan are seeking new avenues for promoting re-myelination in patients with various neuropathies.

The new study, “The Prohibitin Family and Their Function in Myelination and Axonal Health,” is funded with a five-year grant totaling $1,704,000 from the National Institute of Neurological Disorders and Stroke.

Co-authors from the Jacobs School of Medicine and Biomedical Sciences are:

• Lawrence Wrabetz, MD, professor of neurology and biochemistry and director of the HJKRI
• Bogdan K. Beirowski MD, PhD, assistant professor of biochemistry and principal investigator at the HJKRI

Other co-authors are:

• Jun Qu, PhD, associate professor in the School of Pharmacy and Pharmaceutical Sciences
• G. Ekin Atilla-Gokcumen, PhD, J. Solo assistant professor of chemistry

The HJKRI — one of only a handful of centers focused exclusively on myelin, myelin disorders and their treatment — is part of UB’s New York State Center of Excellence in Bioinformatics and Life Sciences.

It was established in 2008 by Buffalo Bills Hall of Fame quarterback Jim Kelly and his wife, Jill, after their infant son, Hunter, was diagnosed with the inherited, fatal disorder Krabbe Leukodystrophy as an infant. He died in 2005 at the age of 8.