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Genes Dev. 2008 Jun 15;22(12):1647-61. doi: 10.1101/gad.1638008.

Phosphatidic acid mediates demyelination in Lpin1 mutant mice.

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  • 1Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.

Abstract

Lipids play crucial roles in many aspects of glial cell biology, affecting processes ranging from myelin membrane biosynthesis to axo-glial interactions. In order to study the role of lipid metabolism in myelinating glial cells, we specifically deleted in Schwann cells the Lpin1 gene, which encodes the Mg2+-dependent phosphatidate phosphatase (PAP1) enzyme necessary for normal triacylglycerol biosynthesis. The affected animals developed pronounced peripheral neuropathy characterized by myelin degradation, Schwann cell dedifferentiation and proliferation, and a reduction in nerve conduction velocity. The observed demyelination is mediated by endoneurial accumulation of the substrate of the PAP1 enzyme, phosphatidic acid (PA). In addition, we show that PA is a potent activator of the MEK-Erk pathway in Schwann cells, and that this activation is required for PA-induced demyelination. Our results therefore reveal a surprising role for PA in Schwann cell fate determination and provide evidence of a direct link between diseases affecting lipid metabolism and abnormal Schwann cell function.

PMID:
18559480
[PubMed - indexed for MEDLINE]
PMCID:
PMC2428062
Free PMC Article

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