Phosphatidic acid mediates demyelination in Lpin1 mutant mice

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...

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Bibliographic Details
Published in:Genes & development 2008-06, Vol.22 (12), p.1647-1661
Main Authors: Nadra, Karim, de Preux Charles, Anne-Sophie, Médard, Jean-Jacques, Hendriks, William T, Han, Gil-Soo, Grès, Sandra, Carman, George M, Saulnier-Blache, Jean-Sébastien, Verheijen, Mark H G, Chrast, Roman
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Cell Differentiation - genetics
Cells, Cultured
Demyelinating Diseases - etiology
Demyelinating Diseases - genetics
Demyelinating Diseases - metabolism
Gene Expression Regulation
Mice
Mice, Inbred BALB C
Mice, Knockout
Myelin Sheath - metabolism
Nuclear Proteins - genetics
Organ Specificity - genetics
Pancreatitis-Associated Proteins
Peripheral Nerves - metabolism
Phosphatidate Phosphatase
Phosphatidic Acids - physiology
Protein Isoforms - genetics
Protein Isoforms - physiology
Proteins - genetics
Proteins - metabolism
Rats
Rats, Sprague-Dawley
Research Paper
Schwann Cells - metabolism
Schwann Cells - physiology
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1638008