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

Hauke Werner, Dr. rer. nat.

Fax: +49-551-3899-758


Proteolipids and mouse models of Pelizaeus-Merzbacher Disease
Hauke Werner, Wiebke Möbius in collaboration with I. Griffiths, Glasgow, Scotland.

Pelizaeus-Merzbacher disease in children (PMD) is a severe, slowly progressive leukodystrophy of early-onset. Common clinical features include nystagmoid eye movements, dystonia, psychomotoric disabilities, cerebellar dysfunction, and diffuse leg and arm atrophy. Over 75% of PMD cases are caused by mutations affecting the gene encoding myelin proteolipid protein (PLP). Disease progression is variable and depends on both, type of mutation and modifier genes. Both, point mutations in and over-expression of PLP, lead to toxic gain-of-function effects in oligodendrocytes (OL), which is clinically more severe than loss-of-function resulting from PLP null mutations.

Figure: Left: Topological model of Myelin Proteolipid Protein (PLP, black). Amino acids mutated in human Pelizaeus-Merzbacher disease patients are depicted in red. Right: The PLPjimpy mouse model for human Pelizaeus-Merbacher disease at young age (top), and close to premature death in a spastic attack (below).

In mouse models of PMD and other leukodystrophies, the inability to assemble a threshold amount of myelin results in a characteristic behavioral phenotype, a body tremor beginning in the third postnatal week, demonstrating that myelin is required for fine-tuning motor control and posture reflexes. Loss of myelin also causes seizures and often premature death. We have studied the most abundant structural proteins of myelin in vivo by analyzing specific developmental abnormalities of mouse mutants with single-gene defects. The mutant mouse alleles PLPjimpy, PLPrumpshaker, and transgenic overexpressors have become an important tool for both basic and pre-clinical research and provide animal models for equivalent human genetic diseases. A toxic gain-of-function effect emerges as the major cause of dysmyelination and cell death.

Knockout mice lacking any PLP expression are myelinated almost normally, and their myelin ultrastructure suggests that myelin proteolipids contribute to the compact CNSmyelin architecture as a molecular "strut" in the extracellular membrane apposition zone. By motor and behavior assays, these mice lack obvious motor deficits during development. However, later in life they develop axonal swellings throughout the CNS, causing widespread neurodegeneration within several months, as judged by electron microscopic analysis. The associated motor defects differ from those of dysmyelinated mice. Fiber degeneration, mainly affecting small-caliber axons, appears to be secondary to axonal transport impairments. Taken together with similar observations in mice lacking CNP1 expression in oligodendrocytes, this suggests that the long-term integrity of myelinated axons depends critically on local support by myelinating glia.

Detailed information in:

  • 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 PubMed

  • Proteolipid protein is required for transport of sirtuin 2 into CNS myelin.
    Werner HB, Kuhlmann K, Shen S, Uecker M, Schardt A, Dimova K, Orfaniotou F, Dhaunchak A, Brinkmann BG, Möbius W, Guarente L, Casaccia-Bonnefil P, Jahn O, Nave KA

    J Neurosci 2007 27:7717-30 PubMed

  • Perturbed interactions of mutant proteolipid protein/DM20 with cholesterol and lipid rafts in oligodendroglia: implications for dysmyelination in spastic paraplegia.
    Krämer-Albers EM, Gehrig-Burger K, Thiele C, Trotter J, Nave KA

    J Neurosci 2006  26:11743-52 PubMed

  • Assembly of CNS myelin in the absence of proteolipid protein.
    Klugmann M., Schwab M.H., Puhlhofer A., Schneider A., Zimmermann F., Griffiths I.R., and Nave K.-A.

    Neuron 1997 18:59-70 PubMed

  • Mouse models of myelin diseases.
    Werner H., Jung M., Klugmann M., Sereda M., Griffiths I.R., and Nave K.-A.

    Brain Pathol. 1998 8:771-93 PubMed

  • Axonal swellings and degeneration in mice lacking the major proteolipid of myelin.
    Griffiths I.R., Klugmann M., Anderson T., Yool D., Thomson C., Schwab M.H., Schneider A., Zimmermann F., McCulloch M., Nadon N., and Nave K.-A.

    Science 1998 280:1610-3 PubMed

  • Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia.
    Edgar, J.M., McLaughlin, M., Yool, D., Zhang, S.-C., Fowler, J., Montague, P., Barrie, J.A., McCulloch, M.C., Duncan, I.D., Garbern, J., Nave, K.-A., and Griffiths, I.R.

    J. Cell Biol. 2004 166, 121-131. PubMed

The following external links provide more information on myelin, proteolipid protein, and Pelizaeus-Merzbacher disease. We are not responsible for any external content.

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