Dynamic equilibria of membrane microdomains and protein modifications in central nervous system myelin

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The myelin sheath is a membranous spiral that wraps around the axons (nerves) of the central nervous system (CNS), and enables them to transmit impulses efficiently. Diseases of myelin such as multiple sclerosis and Pelizaeus-Merzbacher affect CNS function and are extremely debilitating. The CNS myelin is formed by extensions of membranes of cells called oligodendrocytes - one oligodendrocyte can enwrap several different nerve fibers. The formation of myelin in early childhood is a complex process that occurs in stages. At each stage, gene expression must be strictly controlled to produce the right amounts of many different components that then need to be delivered to the correct location in the cell. Even in the mature CNS, there is constant turnover and replenishment of myelin proteins and lipids. When one looks at myelin in the electron microscope, one sees mainly compact myelin, but also less compact loop regions. An even closer look indicates that myelin consists of different "microdomains" that can be "dissected" out by biochemical extractions with detergents. These microdomains differ not so much in composition of their constituent proteins and lipids, but rather in how these proteins have been modified by different enzymes after synthesis (this last process is called "post-translational modification"). Our research aims to understand how the modification pattern of CNS myelin proteins varies dynamically during development, and spatially in normal adult myelin. We look at the pattern of protein changes as an oligodendrocyte matures, primarily phosphorylation and deimination, because we consider that the balance of these changes is crucial to maintaining a healthy myelin sheath. As part of this endeavour, we look at the structures of one of the modifying enzymes (peptidylarginine deiminase) and of a major constituent protein (proteolipid protein) using a variety of complementary biochemical and biophysical techniques. The peptidylarginine deiminase enzyme represents a possible therapeutic target for multiple sclerosis, and potential inhibitors shall be evaluated functionally and structurally.