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A Signaling Lipid Associated with Alzheimer's Disease Promotes Mitochondrial Dysfunction

Kennedy, Michael A
Moffat, Tia C
Gable, Kenneth
Ganesan, Suriakarthiga
Johnston, Anne
Nislow, Corey
Giaever, Guri
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Published in Scientific reports. 2016, vol. 6, 19332
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.
Keywords Alzheimer Disease/genetics/metabolism/pathologyAmyloid beta-Peptides/metabolismCell LineCellsCulturedCeramides/metabolismGene Expression ProfilingHumansLipid Metabolism/geneticsMechanistic Target of Rapamycin Complex 2Membrane PotentialMitochondrialMitochondria/genetics/metabolismMultiprotein Complexes/metabolismNeurons/metabolismOpen Reading FramesOxidative StressReactive Oxygen Species/metabolismSignal TransductionTOR Serine-Threonine Kinases/metabolism
PMID: 26757638
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Research group Groupe Loewith
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KENNEDY, Michael A et al. A Signaling Lipid Associated with Alzheimer's Disease Promotes Mitochondrial Dysfunction. In: Scientific Reports, 2016, vol. 6, p. 19332. doi: 10.1038/srep19332 https://archive-ouverte.unige.ch/unige:103224

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Deposited on : 2018-03-27

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