Investigating the role of Cd59 in oligodendrocyte development

About This Grant

Project Summary/Abstract Myelin is a lipid-rich sheath that wraps axons within the vertebrate nervous system to increase the speed of action potential propagation and provide metabolic support to the axon. The myelin sheath is generated by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Developmental myelination is a dynamic and complex process. Some of the cellular interactions driving myelinating glial cell development have been characterized, but a full understanding of the molecular mechanisms that mediate this process is lacking. Genetic disorders affecting the white matter, termed leukodystrophies, result in absent or abnormal myelin development, and are most often diagnosed in infants and children. On the other hand, demyelinating disorders, such as multiple sclerosis, involve the breakdown of existing myelin and can be caused by direct destruction of the oligodendrocyte or occur as a result of neuronal damage or degeneration. All of these disorders can lead to cognitive defects, muscle weakness, motor problems and more. Treatments are limited, and efforts are underway to better understand the mechanisms driving myelin development in order to develop remyelinating therapies. Using publicly available RNA sequencing and proteomics data, the gene cd59 was identified as highly expressed in Schwann cells and oligodendrocytes during development. Cd59 encodes the small GPI-anchored protein Cd59, which is best known for inhibition of complement-induced cell lysis of host cells. Recent studies have also implicated a non-GPI anchored isoform of Cd59 in facilitation of SNARE complex assembly and exocytosis in various cell types. The Kucenas lab generated cd59 mutant zebrafish using CRISPR-Cas9 genome editing and found that Schwann cells of cd59 mutant larvae over-proliferate but display hypomyelination and disrupted node of Ranvier development. This proposal aims to decipher the role of Cd59 in oligodendrocyte development. Aim 1 will further investigate the presence of paranodal bridges linking individual myelin sheaths as seen in preliminary studies and will examine the development and maturation of nodes of Ranvier in cd59 mutants. Aim 2 will focus on understanding the mechanisms by which Cd59 regulates oligodendrocyte development, investigating the role of Cd59 in oligodendrocyte exocytosis and whether this is mediated by a non-GPI anchored isoform as shown in other cell types. This proposal will be conducted in the Kucenas lab at the University of Virginia (UVA). The Kucenas lab has a strong track record of discovering novel mechanisms of glial cell development, and UVA is well known for its expansive glial biology community. Completion of this fellowship will include a mastery of various technical skills, such as molecular biology and advanced microscopy, and drive intellectual and professional growth as an independent scientific researcher.