Srf1 Is a Novel Regulator of Phospholipase D Activity and Is Essential to Buffer the Toxic Effects of C16:0 Platelet Activating Factor

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dc.contributor.author Kennedy, Michael A.
dc.contributor.author Kabbani, Nazir
dc.contributor.author Lambert, Jean-Philippe
dc.contributor.author Swayne, Leigh Anne
dc.contributor.author Ahmed, Fida
dc.contributor.author Figeys, Daniel
dc.contributor.author Bennett, Steffany A. L.
dc.contributor.author Bryan, Jennnifer
dc.contributor.author Baetz, Kristin
dc.date.accessioned 2016-03-15T17:22:20Z
dc.date.available 2016-03-15T17:22:20Z
dc.date.copyright 2011 en_US
dc.date.issued 2011-02-10
dc.identifier.citation Kennedy, M.A., Kabbani, N., Lambert, J-P., Swayne, L.A., Ahmed, F., Figeys, D., ... Baetz, K. (2011). Srf1 Is a Novel Regulator of Phospholipase D Activity and Is Essential to Buffer the Toxic Effects of C16:0 Platelet Activating Factor. PLoS Genetics, 7(2), 1-12. en_US
dc.identifier.uri http://dx.doi.org/10.1371/journal.pgen.1001299
dc.identifier.uri http://hdl.handle.net/1828/7083
dc.description.abstract During Alzheimer’s Disease, sustained exposure to amyloid-b42 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 GFPSpo14 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-b42. en_US
dc.description.sponsorship This work was supported by an Early Researcher Award from the Ontario Government to KB; operating support from the Canadian Institute of Health Research (CIHR, MOP 89999) to SALB, DF, and KB; a Strategic Training Initiative in Health Research (STIHR)/CIHR Training Grant in Neurodegenerative Lipidomics to SALB, DF, and KB; and operating support from the Natural Sciences and Engineering Research Council (NSERC) to JB. KB is a Canada Research Chair (CRC) in Chemical and Functional Genomics. DF is a CRC in Proteomics and Systems Biology. MAK and LAS were supported by an Institute of Aging and STIHR/CIHR Training Grant in Neurodegenerative Lipidomics post-doctoral fellowship. LAS was also supported by the Heart and Stroke Foundation Centre for Stroke Recovery and a Vision 2010 (Ministry of Research and Innovation, Ontario, University of Ottawa, Parkinson’s Research Network) postdoctoral fellowship. FA was supported by a NSERC Canadian Graduate Vanier Scholarship. J-PL was supported by an Ontario Graduate Scholarship. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. en_US
dc.language.iso en en_US
dc.publisher PLoS Genetics en_US
dc.rights Attribution 2.5 Canada *
dc.rights.uri http://creativecommons.org/licenses/by/2.5/ca/ *
dc.title Srf1 Is a Novel Regulator of Phospholipase D Activity and Is Essential to Buffer the Toxic Effects of C16:0 Platelet Activating Factor en_US
dc.type Article en_US
dc.description.scholarlevel Faculty en_US
dc.description.reviewstatus Reviewed en_US

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