Characterization of Substrate Preference for Slc1p and Cst26p in Saccharomyces cerevisiae Using Lipidomic Approaches and an LPAAT Activity Assay

Shui, Guanghou; Guan, Xue Li; Gopalakrishnan, Pradeep; Xue, Yangkui; Goh, Joyce Sze Yuin; Yang, Hongyuan; Wenk, Markus R.

doi:10.1371/journal.pone.0011956

Cited by 37 publications

(45 citation statements)

References 37 publications

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“…Full-scan, selected ion recording, and daughter scan mode were used for qualitative analyses. Quantitative PA analyses were made based on MS/MS MRM as described (51). Briefly, MRM transitions for each individual PA were determined based on PA standards obtained from Avanti Polar Lipids.…”

Section: Methodsmentioning

confidence: 99%

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Tabet

Moutin

Becker

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.F ragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, is due to the transcriptional inactivation of the Fragile X Mental Retardation 1 gene (FMR1) (1, 2). The FMR1 knockout (KO) mouse (Fmr1 −/y ) replicates phenotypes similar to human symptoms-including autistic-like behaviors, cognitive deficits, and hyperactivity-as well as abnormal dendritic spine morphology (3). FMR1 encodes Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein associated to polyribosomes and involved in the translational control of mRNAs important for synaptic plasticity (4). Consistent with a posttranscriptional function, the absence of FMRP in Fmr1 −/y mouse causes abnormal signaling of group 1 metabotropic glutamate receptors (mGluRI), leading to several forms of abnormal synaptic plasticity that rely on protein translation (5, 6). Protein expression analyses confirmed a role of FMRP in neuronal translational control (7), but the extent of this control remains unclear. Although several studies focusing on individual mRNA targets (e.g., Fmr1, Map1b, Psd95, App, etc.) suggest specific control by FMRP (2), studies of global translation, including in vivo labeling in the Fmr1 −/y mouse (8), showed thousands of neuronal proteins deregulated in the absence of FMRP, pointing toward a general translational derepression. Studies seeking to identify the transcripts controlled by FMRP identified can...

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Section: Methodsmentioning

confidence: 99%

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Tabet

Moutin

Becker

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Separation and quantification of individual lipids was performed using an Agilent 1200 high-performance liquid chromatography (HPLC) system and a 3200 Q-Trap mass spectrometer (Applied Biosystems) (Chan et al, 2008;Shui et al, 2010). The HPLC system is made up of an Agilent 1200 binary pump, an Agilent 1200 thermo sampler and an Agilent 1200 column oven HPLC conditions Luna 3u silica column (inner diameter 150 ϫ 2.0 mm); mobile phase A (chloroform/methanol/ammonium hydroxide, 89.5: 10:0.5), B (chloroform/methanol/ammonium hydroxide/water, 55:39:0.5: 5.5); flow rate 350 l/min; 5% B for 3 min, then linearly changed to 30% B in 24 min and maintained for 5 min, and then linearly changed to 70% B in 5 min and maintained for 7 min.…”

Section: Methodsmentioning

confidence: 99%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

111

100

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The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.

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“…Lipidomics approaches have therefore been used to investigate lipid metabolism at the cellular level, in animal studies and increasingly in the human pathophysiological context [33]–[42]. In the present study we have undertaken the first lipidomics analysis of human PD tissues.…”

Section: Introductionmentioning

confidence: 99%

Lipid Pathway Alterations in Parkinson's Disease Primary Visual Cortex

et al. 2011

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BackgroundWe present a lipidomics analysis of human Parkinson's disease tissues. We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.Methodology/Principal FindingsUsing liquid chromatography mass spectrometry lipidomics techniques for an initial screen of 200 lipid species, significant changes in 79 sphingolipid, glycerophospholipid and cholesterol species were detected in the visual cortex of Parkinson's disease patients (n = 10) compared to controls (n = 10) as assessed by two-sided unpaired t-test (p-value <0.05). False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05). By contrast, changes in 17 and 12 lipid species were identified in the Parkinson's disease amygdala and anterior cingulate cortex, respectively, compared to controls; none of which remained significant after false discovery rate analysis. Using gas chromatography mass spectrometry techniques, 6 out of 7 oxysterols analysed from both non-enzymatic and enzymatic pathways were also selectively increased in the Parkinson's disease visual cortex. Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.Conclusions/SignificanceThe data indicate that changes in lipid metabolism occur in the Parkinson's disease visual cortex in the absence of obvious pathology. This suggests that normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms, such as visual hallucinations, that are experienced by a majority of Parkinson's disease patients.

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Characterization of Substrate Preference for Slc1p and Cst26p in Saccharomyces cerevisiae Using Lipidomic Approaches and an LPAAT Activity Assay

Cited by 37 publications

References 37 publications

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Lipid Pathway Alterations in Parkinson's Disease Primary Visual Cortex

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