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GENES & DEVELOPMENT 22:1647-1661, 2008
©2008 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Phosphatidic acid mediates demyelination in Lpin1 mutant mice

Karim Nadra1, Anne-Sophie de Preux Charles1,2, Jean-Jacques Médard1, William T. Hendriks3, Gil-Soo Han4, Sandra Grès5, George M. Carman4, Jean-Sébastien Saulnier-Blache5, Mark H.G. Verheijen3, and Roman Chrast1,6

1 Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland; 2 Graduate Program in Neurosciences, University of Lausanne, 1015 Lausanne, Switzerland; 3 Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands; 4 Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA; 5 INSERM, U858/I2MR, Department of Metabolism and Obesity, BP 84225, 31432 Toulouse Cedex 4, France

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.

[Keywords: Schwann cells; myelin; peripheral neuropathy; lipid metabolism; phosphatidic acid]

Received November 29, 2007; revised version accepted April 18, 2008.

6 Corresponding author.

E-MAIL roman.chrast{at}unil.ch; FAX 41-21-6925455.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1638008.


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