Phosphatidic acid mediates demyelination in Lpin1 mutant mice

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 Mg 2+ -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] Supplemental material is available at http://www.genesdev.org.

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

“…Conversion of PA to DAG is required for synthesis of triglyceride and phospholipids that are major constituents of cell membranes. Mutations in lipin 1 PAP activity would be predicted to increase the cellular PA concentration, which may be toxic and/or activate inflammatory MAPK signaling cascades (Nadra et al 2008). PA also activates mTORC1 kinase (Sun and Chen 2008;Mitra et al 2013), which has been linked to development of muscle injury and myopathy (Castets et al 2013) Leu635Pro (*P < 0.05, t-test).…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…Another potential mechanism for demyelination is described in recent reports showing that Schwann cell specific inactivation of the Lpin1 gene caused myelin degradation and Schwann cell dedifferentiation (Nadra et al, 2008). Lipin1 is an enzyme that catalyzes the dephosphorylation of phosphatidic acid, which was found at elevated levels in the mutant nerves.…”

A Hypomorphic Mutation in Lpin1 Induces Progressively Improving Neuropathy and Lipodystrophy in the Rat

“…This indicated that the neuropathy present in Lpin1 fld/fld mice is a direct consequence of the absence of Lipin 1 within SCs. Moreover, SC-specific deletion of Lpin1 also revealed an interaction between PA and the MEK-ERK signaling pathway mediating SC de-differentiation and proliferation (2). In addition, mutant mice (Lpin1…”

“…Lipin 1 plays a crucial role in lipid metabolism in multiple cell types including glia, adipocytes, myocytes, and hepatocytes (1)(2)(3)(4). Previous studies have shown that Lipin 1 is a Mg 2ϩ -dependent phosphatidate phosphatase (PAP1) 5 enzyme catalyzing the dephosphorylation of phosphatidic acid (PA), yielding inorganic phosphate and diacylglycerol needed for the synthesis of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine (5)(6)(7)(8).…”

“…The mammalian Lipin protein family consists of three members, Lipin 1, Lipin 2, and Lipin 3 (9), which are encoded by transcripts with specific tissue expression patterns (5). Lpin1 is expressed at high levels in white adipose tissue (WAT) and muscle (5), and is also present in other tissues including peripheral nerve (2). Alternative splicing of Lpin1 generates two Lipin 1 isoforms that play distinct, but complementary, roles in adipogenesis: Lipin 1␣, which affects adipocyte differentiation, and Lipin 1␤, which induces lipogenic gene expression (10).…”