A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast.
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.
Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Michael A
MA
Kennedy
Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Kenneth
K
Gable
Department of Molecular Biology and Swiss National Center for Competence in Research Programme Chemical Biology, University of Geneva, Geneva, Switzerland.
Karolina
K
Niewola-Staszkowska
Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Utrecht, The Netherlands.
Susana
S
Abreu
Eastern Cereal and Oilseed Research Centre, Agriculture and Agri-Food Canada, Ottawa, Ontario, Canada.
Anne
A
Johnston
Eastern Cereal and Oilseed Research Centre, Agriculture and Agri-Food Canada, Ottawa, Ontario, Canada.
Linda J
LJ
Harris
Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Utrecht, The Netherlands.
Fulvio
F
Reggiori
Department of Molecular Biology and Swiss National Center for Competence in Research Programme Chemical Biology, University of Geneva, Geneva, Switzerland.
Robbie
R
Loewith
Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Teresa
T
Dunn
Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Steffany A L
SA
Bennett
Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Kristin
K
Baetz
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000096:biosynthesis / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010767:Phosphorylcholine / Q000633:toxicity*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002518:Ceramides; D046912:Multiprotein Complexes; D019269:Phosphatidylinositol 4,5-Diphosphate; D029701:Saccharomyces cerevisiae Proteins; D010767:Phosphorylcholine; D017853:Phosphotransferases (Alcohol Group Acceptor); C489795:MSS4 protein, S cerevisiae; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases