A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast

Kennedy, Michael A; Gable, Kenneth; Niewola-Staszkowska, Karolina; Abreu, Susana; Johnston, Anne; Harris, Linda J; Reggiori, Fulvio; Loewith, Robbie Joséph; Dunn, Teresa; Bennett, Steffany A L; Baetz, Kristin

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Title		A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast
Authors		Kennedy, Michael A Gable, Kenneth Niewola-Staszkowska, Karolina Abreu, Susana Johnston, Anne Harris, Linda J Reggiori, Fulvio Loewith, Robbie Joséph Dunn, Teresa Bennett, Steffany A L Baetz, Kristin show all authors [1 - 11]
Published in		PLOS Genetics. 2014, vol. 10, no. 1, p. 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		DOI: 10.1371/journal.pgen.1004010 PMID: 24465216
Full text		Article (Published version) (1.9 MB) - Free access
Structures		Faculté des sciences / Section de biologie / Département de biologie moléculaire Centres et instituts / Institut de génétique et de génomique
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. https://archive-ouverte.unige.ch/unige:103231