Investigation of the Mechanism of Myelin Formation

Current: ___________ (Open project!)
Alumni: Andrew Molina

The myelin sheath is an insulating, compacted, multilamellar biological membrane that facilitates the rapid propagation of action potentials down the axons of neurons via saltatory conduction. It is critical for normal physiological function, as demyelinating diseases such as multiple sclerosis lead to severe physical and mental impairment and even death.

Recently, University of Chicago neurobiologist Sara Szuchet has found compelling in vivo evidence that the long-established mechanism for the formation of central nervous system (CNS) myelin, in which a wrapped oligodendrocyte membrane becomes the final myelin, has serious flaws. To address these flaws in the current model, Szuchet has proposed a new model involving (1) the preformation of myelin membrane tubules that are trafficked to the neuronal axon, where they (2) undergo a transition from tubular to lamellar form and thus form the final compact myelin sheath (Szuchet et al. J. Struct. Biol. 2015, 190, 56-72.).

To investigate this mechanism, we designed in vitro experiments to probe the biophysical interactions of myelin lipids as they (1) self-assemble into tubules and (2) transition into lamellar form. Specifically, using TEM imaging, we have observed the self-assembly of tubules consisting of 100% galactosylceramide (GalCer), a fundamental glycolipid of CNS myelin. We have similarly investigated how 2-component systems of GalCer/Cholesterol and GalCer/Plasmalogen transition from stable tubule structures to larger aggregates of lower curvature upon decreasing GalCer concentration. The stable tubules of these in vitro systems observed at higher GalCer concentrations align with the in silico results of coarse-grained simulations (Voth Group, University of Chicago) and the tubules observed in vivo in ovine oligodendrocytes by Szuchet (Szuchet et al., 2015), suggesting that these structures of major myelin lipids can be stable precursors for myelination. Using fluid-cell AFM, we have begun to investigate how these self-assembled tubules interact with supported lipid bilayers in HEPES buffer solution (pH 7.4) with hopes of observing a fusion event between the structures that would be experimental evidence of the proposed Szuchet model for the biological mechanism of myelin formation.