Study to Identify Novel Cellular Mediators in Myelination Process

She and her team will assess why the myelination process fails when these proteins are defective. They plan to seek new avenues for promoting re-myelination in patients with various neuropathies.

Funded with a new five-year $1.7 million grant from the National Institute of Neurological Disorders and Stroke, this project, “Laminin Receptors and Signals in Schwann Cells,” builds on more than 25 years of research. The National Institutes of Health have funded earlier phases of the same project for the past decade.

“Our studies can reveal strategies to bypass genetic defects in order to repair myelin and cure devastating neurological diseases,” says Feltri, who also is a faculty member in the University at Buffalo’s neuroscience and genetics, genomics and bioinformatics (GGB) programs.

Myelin is the fatty substance that surrounds axons in the nervous system and allows them to signal effectively.

When myelin fails to synthesize or breaks down, a number of neurological diseases result, including congenital muscular dystrophies; multiple sclerosis; leukodystrophies, such as Krabbe disease; and peripheral dysmyelinating neuropathies.

Feltri has been exploring how the extracellular environment governs myelination and influences the outcome of myelin diseases.

Before myelination can occur, axon-enfolding Schwann cells must first perform the developmental step of radial sorting of axons, but impaired laminin signaling arrests this process.

“We now propose to address three fundamental questions and roadblocks to our understanding of sorting and myelination,” says Feltri.

Her team will explore:

• how two types of proteins at the basal surface of Schwann cells (laminins, or binding proteins, and integrins, or proteins that mediate cellular interactions) promote interaction with axons at the opposite surface
• how signals from laminins are integrated with signals from axonal proteins called neuregulins
• the process by which myelinating glial cells contact and wrap axons
  

Feltri’s team previously discovered some of the molecules — receptors and adhesive molecules — that cells involved in peripheral nerve myelination use to communicate.

The UB researchers showed that axonal sorting is a multistep process. They found that the early steps of axonal recognition, segregation and wrapping require specific laminin receptors: a6ß1 and a7ß1 integrins and Rac1 Rho GTPase.

Additionally, they learned that pro-myelinating Schwann cells need the laminin receptor dystroglycan to perform a subsequent step in the process: the detachment of large-caliber axons.

The researchers will use a combination of techniques, including:

• mouse models (in collaboration with Lawrence Wrabetz, MD, professor of neurology and biochemistry, director of the HJKRI and a GGB faculty member; and Nicholas J. Silvestri, MD, assistant professor of clinical neurology)
• sophisticated co-culture systems, essentially “myelin in a dish”
• advanced proteomic techniques (in collaboration with Jun Qu, PhD, associate professor of pharmaceutical sciences and a GGB faculty member)

The research team in the Feltri lab includes Dominique Ameroso, a biochemistry master’s student in the neuroscience program; Kathleen Catignas, Monica Ghidinelli and Marilena Palmisano, all PhD students; and Yannick Poitelon, a post-doctoral research scientist.