title: Srf1 is a novel regulator of phospholipase D activity and is essential to buffer the toxic effects of C16:0 platelet activating factor.
abstract: During Alzheimer's Disease, sustained exposure to amyloid-β₄₂ oligomers perturbs metabolism of ether-linked glycerophospholipids defined by a saturated 16 carbon chain at the sn-1 position. The intraneuronal accumulation of 1-O-hexadecyl-2-acetyl-sn-glycerophosphocholine (C16:0 PAF), but not its immediate precursor 1-O-hexadecyl-sn-glycerophosphocholine (C16:0 lyso-PAF), participates in signaling tau hyperphosphorylation and compromises neuronal viability. As C16:0 PAF is a naturally occurring lipid involved in cellular signaling, it is likely that mechanisms exist to protect cells against its toxic effects. Here, we utilized a chemical genomic approach to identify key processes specific for regulating the sensitivity of Saccharomyces cerevisiae to alkyacylglycerophosphocholines elevated in Alzheimer's Disease. We identified ten deletion mutants that were hypersensitive to C16:0 PAF and five deletion mutants that were hypersensitive to C16:0 lyso-PAF. Deletion of YDL133w, a previously uncharacterized gene which we have renamed SRF1 (Spo14 Regulatory Factor 1), resulted in the greatest differential sensitivity to C16:0 PAF over C16:0 lyso-PAF. We demonstrate that Srf1 physically interacts with Spo14, yeast phospholipase D (PLD), and is essential for PLD catalytic activity in mitotic cells. Though C16:0 PAF treatment does not impact hydrolysis of phosphatidylcholine in yeast, C16:0 PAF does promote delocalization of GFP-Spo14 and phosphatidic acid from the cell periphery. Furthermore, we demonstrate that, similar to yeast cells, PLD activity is required to protect mammalian neural cells from C16:0 PAF. Together, these findings implicate PLD as a potential neuroprotective target capable of ameliorating disruptions in lipid metabolism in response to accumulating oligomeric amyloid-β₄₂.
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kennedy
authors.forename: Nazir
authors.initials: N
authors.lastname: Kabbani
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Swayne
authors.forename: Fida
authors.initials: F
authors.lastname: Ahmed
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: Jennnifer
authors.initials: J
authors.lastname: Bryan
authors.forename: Kristin
authors.initials: K
authors.lastname: Baetz
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D002460:Cell Line; D020404:Glycerophospholipids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C558444:1-O-hexadecylglycerophosphocholine; D020404:Glycerophospholipids; D010972:Platelet Activating Factor; D029701:Saccharomyces cerevisiae Proteins; C558445:Srf1 protein, S cerevisiae; C037145:1-hexadecyl-2-acetyl-glycero-3-phosphocholine; D010739:Phospholipase D