title: A Signaling Lipid Associated with Alzheimer's Disease Promotes Mitochondrial Dysfunction.
abstract: Fundamental changes in the composition and distribution of lipids within the brain are believed to contribute to the cognitive decline associated with Alzheimer's disease (AD). The mechanisms by which these changes in lipid composition affect cellular function and ultimately cognition are not well understood. Although "candidate gene" approaches can provide insight into the effects of dysregulated lipid metabolism they require a preexisting understanding of the molecular targets of individual lipid species. In this report we combine unbiased gene expression profiling with a genome-wide chemogenomic screen to identify the mitochondria as an important downstream target of PC(O-16:0/2:0), a neurotoxic lipid species elevated in AD. Further examination revealed that PC(O-16:0/2:0) similarly promotes a global increase in ceramide accumulation in human neurons which was associated with mitochondrial-derived reactive oxygen species (ROS) and toxicity. These findings suggest that PC(O-16:0/2:0)-dependent mitochondrial dysfunction may be an underlying contributing factor to the ROS production associated with AD.
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, KlH 8M5 Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kennedy
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, KlH 8M5 Canada.
authors.forename: Tia C
authors.initials: TC
authors.lastname: Moffat
authors.affiliation: Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20184-4799, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Gable
authors.affiliation: Department of Biological Sciences, University of Calgary, AB, T2N 1N4 Canada.
authors.forename: Suriakarthiga
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Molecular Biology and Swiss National Center for Competence in Research Programme Chemical Biology, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Niewola-Staszkowska
authors.affiliation: Ottawa Research and Development Centre, Agriculture and Agri-Food Canada, Ottawa, Ontario K1A 0C6, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Johnston
authors.affiliation: University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.affiliation: Ottawa Research and Development Centre, Agriculture and Agri-Food Canada, Ottawa, Ontario K1A 0C6, Canada.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Harris
authors.affiliation: Department of Molecular Biology and Swiss National Center for Competence in Research Programme Chemical Biology, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Robbie
authors.initials: R
authors.lastname: Loewith
authors.affiliation: Department of Biological Sciences, University of Calgary, AB, T2N 1N4 Canada.
authors.forename: Vanina
authors.initials: V
authors.lastname: Zaremberg
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, KlH 8M5 Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20184-4799, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Dunn
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, KlH 8M5 Canada.
authors.forename: Steffany A L
authors.initials: SAL
authors.lastname: Bennett
authors.affiliation: Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, KlH 8M5 Canada.
authors.forename: Kristin
authors.initials: K
authors.lastname: Baetz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D000076225:Mechanistic Target of Rapamycin Complex 2; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016366:Open Reading Frames; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002518:Ceramides; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases