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 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.
Nadra
Karim
K
Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
de Preux Charles
Anne-Sophie
AS
Médard
Jean-Jacques
JJ
Hendriks
William T
WT
Han
Gil-Soo
GS
Grès
Sandra
S
Carman
George M
GM
Saulnier-Blache
Jean-Sébastien
JS
Verheijen
Mark H G
MH
Chrast
Roman
R
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D000073718:Pancreatitis-Associated Proteins; D010525:Peripheral Nerves / Q000378:metabolism; D010711:Phosphatidate Phosphatase; D010712:Phosphatidic Acids / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology
D009687:Nuclear Proteins; D000073718:Pancreatitis-Associated Proteins; D010712:Phosphatidic Acids; D020033:Protein Isoforms; D011506:Proteins; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase