A major challenge for myelinating glial cells is the temporal and spatial orchestration of myelin membrane biosynthesis and traffic to control the directed growth of the emerging myelin sheath. The cellular process of myelin formation during development is not understood and so is the question, why remyelination in certain pathological conditions of the CNS (such as multiple sclerosis) is blocked or insufficient. We are studying myelin membrane sorting and transport, deciphering the oligodendroglial membrane trafficking pathways involved in myelination and exploring their regulation. We aim to improve the understanding of myelin disease pathomechanisms and to identify new therapeutic targets. Specific topics are:
a) The role of endocytic sorting and recycling in myelin membrane morphogenesis. (See Winterstein et al., 2008)
b) Identification of SNARE proteins controlling specific fusion steps in the myelin transport pathway and myelin membrane extension. (See Feldmann et al., 2009)
c) Cell signalling mechanisms and regulating myelin membrane traffic.
d) Misregulation of myelin protein trafficking as a trigger of pathology in myelin disease.
European Leukodystrophy association (Project “Analysis of myelin membrane trafficking pathways in PLP-related disorders” 2005-2006, University of Mainz (Forschungsfond 2005, Forschungsförderung Stufe 1 2009-2010)
Myelin proteins undergo distinct endocytic sorting and recycling. A shows endocytosed PLP (red) and MAG (green) and their targeting to the same endocytic compartment (yellow). Recycling of these proteins is associated with their appearance in membrane domains of distinct biochemical composition (see Winterstein et al. 2009 and White et al. 2009)
b) SNARE Proteins
We have analysed the expression profile, subcellular localisation and function of SNARE proteins in oligodendroglial cells (see Feldmann et al. 2009, 2011).
Feldmann A, Amphornrat J, Schönherr M, Winterstein C, Möbius W, Ruhwedel T, Danglot L, Nave KA, Galli T, Bruns D, Trotter J, and Krämer-Albers EM (2011) Transport of the Major Myelin Protein PLP is Directed by the R-SNAREs VAMP3 and VAMP7. J. Neurosci., in press.
Krämer-Albers EM and White R (2011) From axon-glial signalling to myelination: The integrating role of oligodendroglial Fyn Kinase. Cell Mol Life Sci. 2011 Jan 5. [Epub ahead of print]. Review.
Feldmann A., Winterstein C., White R., Trotter J., and Krämer-Albers E.M. (2009) Comprehensive Analysis of Expression, Subcellular Localisation and Cognate Pairing of SNARE Proteins in Oligodendrocytes. J. Neurosci. Res., 87: 1760-1772.
Winterstein C., Trotter, J. and Krämer-Albers, E.M. (2008) Distinct endocytic recycling of myelin proteins promotes oligodendroglial membrane remodeling. J. Cell Sci. 121, 834-842.
Krämer-Albers, E.M., Gehrig-Burger, K., Thiele, C., Trotter, J. and Nave, K.A. (2006) Perturbed Interactions of Mutant Proteolipid Protein/DM20 with Cholesterol and Lipid Rafts in Oligodendroglia: Implications for Dysmyelination in Spastic Paraplegia. J. Neurosci. 26: 11743-11752.