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Max-Planck-Gesellschaft
Max-Planck-Institut für Experimentelle Medizin
Prof. Klaus-Armin Nave

Ajit Dhaunchak

Ajit@em.mpg.de

Anke Schardt

Schardt@em.mpg.de

Foteini Orfaniotou

Orfaniotou@em.mpg.de

Hauke Werner, PhD               

Hauke@em.mpg.de


Cell biology of proteolipid protein (PLP/DM20) in myelination

Proteolipid protein (PLP) is the most abundant integral membrane protein of myelin in the central nervous system. PLP comprises 276 amino acid residues and four highly hydrophobic stretches that constitute membrane-spanning domains. A second isoform, termed DM20, is generated by alternative RNA splicing, and lacks 35 residues from an intracellular loop region. PLP acts as a strut within CNS myelin, with its extracellular loop regions defining the exact membrane-to membrane spacing in compact myelin. However, the cell biological function of PLP has been difficult to define.

PLP is associated with detergent insoluble membrane fractions (lipid rafts), but their precise role in myelin membrane formation is unclear. Using laser scanning confocal live imaging and immuno-electron microscopy, we are monitoring epitope-tagged PLP trafficking from the site of biosynthesis at the endoplasmic reticulum towards the gl ial cellular processes. This allows us to determine where myelin components are incorporated into the growing myelin sheath in vitro and in vivo.




Figure: Confocal visualization of ectopic proteolipid protein (PLP) in cultivated oligodendrocytes with an EGFP-tag (in green) and an intracellular marker (in red).



The PLP/DM20 primary structure is highly conserved in tetrapode evolution, suggesting that mutations in the PLP gene are not tolerated. This is supported by the severe neurological consequences in patients with Pelizaeus-Merzbacher disease (defined by mutations in the PLP gene), or in equivalent mouse models. It is thought that mutant PLP fails to adopt the normal three-dimensional structure required to pass the quality control in the endoplasmic reticulum. A detailed mutational analysis with biochemical and cell biological methods aims at identifying amino acids that are crucial for the topology of PLP, and its incorporation into myelin.

A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus Merzbacher disease.
Dhaunchak AS, Nave KA
Proc Natl Acad Sci U S A 2007 104:17813-8



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