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A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast |
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Authors | ![]() | |
Published in | PLOS genetics. 2014, vol. 10, no. 1, e1004010 | |
Abstract | Unbiased lipidomic approaches have identified impairments in glycerophosphocholine second messenger metabolism in patients with Alzheimer's disease. Specifically, we have shown that amyloid-β42 signals the intraneuronal accumulation of PC(O-16:0/2:0) which is associated with neurotoxicity. Similar to neuronal cells, intracellular accumulation of PC(O-16:0/2:0) is also toxic to Saccharomyces cerevisiae, making yeast an excellent model to decipher the pathological effects of this lipid. We previously reported that phospholipase D, a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding protein, was relocalized in response to PC(O-16:0/2:0), suggesting that this neurotoxic lipid may remodel lipid signaling networks. Here we show that PC(O-16:0/2:0) regulates the distribution of the PtdIns(4)P 5-kinase Mss4 and its product PtdIns(4,5)P2 leading to the formation of invaginations at the plasma membrane (PM). We further demonstrate that the effects of PC(O-16:0/2:0) on the distribution of PM PtdIns(4,5)P2 pools are in part mediated by changes in the biosynthesis of long chain bases (LCBs) and ceramides. A combination of genetic, biochemical and cell imaging approaches revealed that PC(O-16:0/2:0) is also a potent inhibitor of signaling through the Target of rampamycin complex 2 (TORC2). Together, these data provide mechanistic insight into how specific disruptions in phosphocholine second messenger metabolism associated with Alzheimer's disease may trigger larger network-wide disruptions in ceramide and phosphoinositide second messenger biosynthesis and signaling which have been previously implicated in disease progression. | |
Keywords | Alzheimer Disease/etiology/metabolism/pathology — Amyloid beta-Peptides/metabolism — Cell Membrane/drug effects — Ceramides/biosynthesis — Humans — Mechanistic Target of Rapamycin Complex 2 — Multiprotein Complexes/biosynthesis/metabolism — Neurons/drug effects — Phosphatidylinositol 4,5-Diphosphate/metabolism — Phosphorylcholine/toxicity — Phosphotransferases (Alcohol Group Acceptor)/biosynthesis — Saccharomyces cerevisiae — Saccharomyces cerevisiae Proteins/biosynthesis — Signal Transduction/drug effects — TOR Serine-Threonine Kinases/biosynthesis/metabolism | |
Identifiers | PMID: 24465216 | |
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Research group | Groupe Loewith | |
Citation (ISO format) | KENNEDY, Michael A et al. A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast. In: PLOS Genetics, 2014, vol. 10, n° 1, p. e1004010. doi: 10.1371/journal.pgen.1004010 https://archive-ouverte.unige.ch/unige:103231 |