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The Alzheimer's Disease Protective P522R Variant of PLCG2
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.27.059600; this version posted April 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. The Alzheimer’s disease protective P522R variant of PLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function. Emily Maguire #1, Georgina E. Menzies#1, Thomas Phillips#1, Michael Sasner2, Harriet M. Williams2, Magdalena A. Czubala3, Neil Evans1, Emma L Cope4, Rebecca Sims5, Gareth R. Howell2, Emyr Lloyd-Evans4, Julie Williams†1,5, Nicholas D. Allen†4 and Philip R. Taylor†*1,3. 1 UK Dementia Research Institute at Cardiff, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, Wales, UK. 2 The Jackson Laboratory, Bar Harbor, Maine 04660, USA. 3 Systems Immunity University Research Institute, Tenovus Building, Heath Park, Cardiff CF 14 4XN, Wales, UK. 4 School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX. 5 MRC Centre for Neuropsychiatric Genetics & Genomics, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, Wales, UK. #†These authors contributed equally *To whom correspondence should be addressed (lead contact): Prof Philip R. Taylor; Tel: +44(0)2920687328; Email: [email protected]. Abstract: Recent genome-wide association studies of Alzheimer’s disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLCγ2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38x10-10, Odds Ratio = 0.68). -
Lysophosphatidic Acid and Its Receptors: Pharmacology and Therapeutic Potential in Atherosclerosis and Vascular Disease
JPT-107404; No of Pages 13 Pharmacology & Therapeutics xxx (2019) xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease Ying Zhou a, Peter J. Little a,b, Hang T. Ta a,c, Suowen Xu d, Danielle Kamato a,b,⁎ a School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia b Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China c Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, St Lucia, QLD 4072, Australia d Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA article info abstract Available online xxxx Lysophosphatidic acid (LPA) is a collective name for a set of bioactive lipid species. Via six widely distributed G protein-coupled receptors (GPCRs), LPA elicits a plethora of biological responses, contributing to inflammation, Keywords: thrombosis and atherosclerosis. There have recently been considerable advances in GPCR signaling especially Lysophosphatidic acid recognition of the extended role for GPCR transactivation of tyrosine and serine/threonine kinase growth factor G-protein coupled receptors receptors. This review covers LPA signaling pathways in the light of new information. The use of transgenic and Atherosclerosis gene knockout animals, gene manipulated cells, pharmacological LPA receptor agonists and antagonists have Gproteins fi β-arrestins provided many insights into the biological signi cance of LPA and individual LPA receptors in the progression Transactivation of atherosclerosis and vascular diseases. -
The Autotaxin–Lysophosphatidic Acid Axis Modulates Histone Acetylation and Gene Expression During Oligodendrocyte Differentiation
The Journal of Neuroscience, August 12, 2015 • 35(32):11399–11414 • 11399 Cellular/Molecular The Autotaxin–Lysophosphatidic Acid Axis Modulates Histone Acetylation and Gene Expression during Oligodendrocyte Differentiation Natalie A. Wheeler,1 James A. Lister,2 and Babette Fuss1 Departments of 1Anatomy and Neurobiology and 2Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 During development, oligodendrocytes (OLGs), the myelinating cells of the CNS, undergo a stepwise progression during which OLG progenitors, specified from neural stem/progenitor cells, differentiate into fully mature myelinating OLGs. This progression along the OLG lineage is characterized by well synchronized changes in morphology and gene expression patterns. The latter have been found to be particularly critical during the early stages of the lineage, and they have been well described to be regulated by epigenetic mechanisms, especially by the activity of the histone deacetylases HDAC1 and HDAC2. The data presented here identify the extracellular factor autotaxin (ATX) as a novel upstream signal modulating HDAC1/2 activity and gene expression in cells of the OLG lineage. Using the zebrafish as an in vivo model system as well as rodent primary OLG cultures, this functional property of ATX was found to be mediated by its lysophospholipase D (lysoPLD) activity, which has been well characterized to generate the lipid signaling molecule lysophosphatidic acid (LPA). More specifically, the lysoPLD activity of ATX was found to modulate HDAC1/2 regulated gene expression during a time window coinciding with the transition from OLG progenitor to early differentiating OLG. In contrast, HDAC1/2 regulated gene expression during the transition from neural stem/progenitor to OLG progenitor appeared unaffected by ATX and its lysoPLD activity. -
(4,5) Bisphosphate-Phospholipase C Resynthesis Cycle: Pitps Bridge the ER-PM GAP
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Topological organisation of the phosphatidylinositol (4,5) bisphosphate-phospholipase C resynthesis cycle: PITPs bridge the ER-PM GAP Shamshad Cockcroft and Padinjat Raghu* Dept. of Neuroscience, Physiology and Pharmacology, Division of Biosciences, University College London, London WC1E 6JJ, UK; *National Centre for Biological Sciences, TIFR-GKVK Campus, Bellary Road, Bangalore 560065, India Address correspondence to: Shamshad Cockcroft, University College London UK; Phone: 0044-20-7679-6259; Email: [email protected] Abstract Phospholipase C (PLC) is a receptor-regulated enzyme that hydrolyses phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at the plasma membrane (PM) triggering three biochemical consequences, the generation of soluble inositol 1,4,5-trisphosphate (IP3), membrane– associated diacylglycerol (DG) and the consumption of plasma membrane PI(4,5)P2. Each of these three signals triggers multiple molecular processes impacting key cellular properties. The activation of PLC also triggers a sequence of biochemical reactions, collectively referred to as the PI(4,5)P2 cycle that culminates in the resynthesis of this lipid. The biochemical intermediates of this cycle and the enzymes that mediate these reactions are topologically distributed across two membrane compartments, the PM and the endoplasmic reticulum (ER). At the plasma membrane, the DG formed during PLC activation is rapidly converted to phosphatidic acid (PA) that needs to be transported to the ER where the machinery for its conversion into PI is localised. Conversely, PI from the ER needs to be rapidly transferred to the plasma membrane where it can be phosphorylated by lipid kinases to regenerate PI(4,5)P2. -
Plasma Lipidome Is Dysregulated in Alzheimer's Disease and Is
Liu et al. Translational Psychiatry (2021) 11:344 https://doi.org/10.1038/s41398-021-01362-2 Translational Psychiatry ARTICLE Open Access Plasma lipidome is dysregulated in Alzheimer’s disease and is associated with disease risk genes Yue Liu1,2, Anbupalam Thalamuthu1, Karen A. Mather1,3, John Crawford1, Marina Ulanova1, Matthew Wai Kin Wong1, Russell Pickford4, Perminder S. Sachdev 1,5 and Nady Braidy 1,6 Abstract Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer’s disease. This study explores a battery of plasma lipids that can differentiate Alzheimer’s disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75–97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled–mass spectrometry (LC–MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ42. -
Role of Phospholipases in Adrenal Steroidogenesis
229 1 W B BOLLAG Phospholipases in adrenal 229:1 R29–R41 Review steroidogenesis Role of phospholipases in adrenal steroidogenesis Wendy B Bollag Correspondence should be addressed Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, USA to W B Bollag Department of Physiology, Medical College of Georgia, Augusta University (formerly Georgia Regents Email University), Augusta, GA, USA [email protected] Abstract Phospholipases are lipid-metabolizing enzymes that hydrolyze phospholipids. In some Key Words cases, their activity results in remodeling of lipids and/or allows the synthesis of other f adrenal cortex lipids. In other cases, however, and of interest to the topic of adrenal steroidogenesis, f angiotensin phospholipases produce second messengers that modify the function of a cell. In this f intracellular signaling review, the enzymatic reactions, products, and effectors of three phospholipases, f phospholipids phospholipase C, phospholipase D, and phospholipase A2, are discussed. Although f signal transduction much data have been obtained concerning the role of phospholipases C and D in regulating adrenal steroid hormone production, there are still many gaps in our knowledge. Furthermore, little is known about the involvement of phospholipase A2, Endocrinology perhaps, in part, because this enzyme comprises a large family of related enzymes of that are differentially regulated and with different functions. This review presents the evidence supporting the role of each of these phospholipases in steroidogenesis in the Journal Journal of Endocrinology adrenal cortex. (2016) 229, R1–R13 Introduction associated GTP-binding protein exchanges a bound GDP for a GTP. The G protein with GTP bound can then Phospholipids serve a structural function in the cell in that activate the enzyme, phospholipase C (PLC), that cleaves they form the lipid bilayer that maintains cell integrity. -
Synthesis of Lysophospholipids
Molecules 2010, 15, 1354-1377; doi:10.3390/molecules15031354 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Synthesis of Lysophospholipids Paola D’Arrigo 1,2,* and Stefano Servi 1,2 1 Dipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy 2 Centro Interuniversitario di Ricerca in Biotecnologie Proteiche "The Protein Factory", Politecnico di Milano and Università degli Studi dell'Insubria, Via Mancinelli 7, 20131 Milano, Italy * Author to whom correspondence should be addressed; E-Mail: paola.d’[email protected]. Received: 17 February 2010; in revised form: 4 March 2010 / Accepted: 5 March 2010 / Published: 8 March 2010 Abstract: New synthetic methods for the preparation of biologically active phospholipids and lysophospholipids (LPLs) are very important in solving problems of membrane–chemistry and biochemistry. Traditionally considered just as second-messenger molecules regulating intracellular signalling pathways, LPLs have recently shown to be involved in many physiological and pathological processes such as inflammation, reproduction, angiogenesis, tumorogenesis, atherosclerosis and nervous system regulation. Elucidation of the mechanistic details involved in the enzymological, cell-biological and membrane-biophysical roles of LPLs relies obviously on the availability of structurally diverse compounds. A variety of chemical and enzymatic routes have been reported in the literature for the synthesis of LPLs: the enzymatic transformation of natural glycerophospholipids (GPLs) using regiospecific enzymes such as phospholipases A1 (PLA1), A2 (PLA2) phospholipase D (PLD) and different lipases, the coupling of enzymatic processes with chemical transformations, the complete chemical synthesis of LPLs starting from glycerol or derivatives. In this review, chemo- enzymatic procedures leading to 1- and 2-LPLs will be described. -
Survival-Associated Metabolic Genes in Colon and Rectal Cancers
Survival-associated Metabolic Genes in Colon and Rectal Cancers Yanfen Cui ( [email protected] ) Tianjin Cancer Institute: Tianjin Tumor Hospital https://orcid.org/0000-0001-7760-7503 Baoai Han tianjin tumor hospital He Zhang tianjin tumor hospital Zhiyong Wang tianjin tumor hospital Hui Liu tianjin tumor hospital Fei Zhang tianjin tumor hospital Ruifang Niu tianjin tumor hospital Research Keywords: colon cancer, rectal cancer, prognosis, metabolism Posted Date: December 4th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-117478/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/42 Abstract Background Uncontrolled proliferation is the most prominent biological feature of tumors. To rapidly proliferate and maximize the use of available nutrients, tumor cells regulate their metabolic behavior and the expression of metabolism-related genes (MRGs). In this study, we aimed to construct prognosis models for colon and rectal cancers, using MRGs to indicate the prognoses of patients. Methods We rst acquired the gene expression proles of colon and rectal cancers from the TCGA and GEO database, and utilized univariate Cox analysis, lasso regression, and multivariable cox analysis to identify MRGs for risk models. Then GSEA and KEGG functional enrichment analysis were utilized to identify the metabolism pathway of MRGs in the risk models and analyzed these genes comprehensively using GSCALite. Results Eight genes (CPT1C, PLCB2, PLA2G2D, GAMT, ENPP2, PIP4K2B, GPX3, and GSR) in the colon cancer risk model and six genes (TDO2, PKLR, GAMT, EARS2, ACO1, and WAS) in the rectal cancer risk model were identied successfully. Multivariate Cox analysis indicated that the models predicted overall survival accurately and independently for patients with colon or rectal cancer. -
G-Proteins in Growth and Apoptosis: Lessons from the Heart
Oncogene (2001) 20, 1626 ± 1634 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc G-proteins in growth and apoptosis: lessons from the heart John W Adams1,2 and Joan Heller Brown*,1 1University of California, San Diego, Department of Pharmacology, 9500 Gilman Drive, 0636, La Jolla, CA, California 92093- 0636, USA The acute contractile function of the heart is controlled by for proliferation of adult cardiomyocytes. In light of the eects of released nonepinephrine (NE) on cardiac these considerations, it is not immediately obvious that adrenergic receptors. NE can also act in a more chronic cardiomyocyte growth and cardiomyocyte death would fashion to induce cardiomyocyte growth, characterized by be responses critical to the normal function of the heart. cell enlargement (hypertrophy), increased protein synth- In fact, the ability of cardiomyocytes to undergo esis, alterations in gene expression and addition of hypertrophic growth, which includes an increase in cell sarcomeres. These responses enhance cardiomyocyte size, is an important adaptive response to a wide range of contractile function and thus allow the heart to conditions that require the heart to work more compensate for increased stress. The hypertrophic eects eectively. As described below, adaptive or compensa- of NE are mediated through Gq-coupled a1-adrenergic tory cardiomyocyte hypertrophy appears to be regulated receptors and are mimicked by the actions of other in large part through stimulation of G-protein coupled neurohormones (endothelin, prostaglandin F2a angiotensin receptors (GPCRs). Often, the ability of cardiomyocytes II) that also act on Gq-coupled receptors. Activation of to function at high capacity under increased workload phospholipase C by Gq is necessary for these responses, cannot be sustained and the heart transitions into a and protein kinase C and MAP kinases have also been condition in which ventricular failure develops. -
Description Cy5 LG Cy3 MI Ratio(Cy3/Cy5) C9orf135
Supplementary Table S2. DNA microarray dataset of top 30 differentially expressed genes and housekeeping genes Up-regulated in SI cancer cells Symbol Description Cy5_LG Cy3_MI Ratio(Cy3/Cy5) C9orf135 Uncharacterized protein C9orf135 1.37 307.8 224.3 KIAA1245 Notch homolog 2 N-terminal like protein 1.82 406.8 223.6 APITD1 Centromere protein S (CENP-S) 2.56 560.3 218.7 PPIL6 Peptidyl-prolyl cis-trans isomerase-like 6 1.85 343.0 185.7 MYCBP2 Probable E3 ubiquitin-protein ligase MYCBP2 2.01 332.1 165.6 ANGPTL4 Angiopoietin-related protein 4 precursor 10.26 1500.1 146.3 C10orf79 Novel protein (Fragment) 2.86 415.5 145.5 NP_653323.1 KPL2 protein isoform 2 1.82 257.5 141.6 ZNF345 Zinc finger protein 345 1.58 215.7 136.8 SIX1 Homeobox protein SIX1 1.59 216.1 136.0 KLHL7 Kelch-like protein 7 1.91 254.4 133.3 TBX1 T-box transcription factor TBX1 1.57 209.0 133.1 PAG1 Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 2.19 290.9 133.0 NOL12 Nucleolar protein 12 1.61 203.7 126.5 ZNF606 Zinc finger protein 606 2.12 267.7 126.0 NFKBIE NF-kappa-B inhibitor epsilon 5.28 658.3 124.7 ZMYND10 Zinc finger MYND domain-containing protein 10 6.85 835.5 121.9 hCG_23177 - 14.94 1758.9 117.7 KIF3A Kinesin-like protein KIF3A 1.94 224.9 116.1 Q9C0K3_HUMAN Actin-related protein Arp11 3.38 368.0 108.9 NP_056263.1 DPCD protein 2.61 270.5 103.7 GBP1 Interferon-induced guanylate-binding protein 1 1.46 149.1 102.3 NP_660151.2 NAD(P) dependent steroid dehydrogenase-like 1.35 137.4 101.5 NP_689672.2 CDNA FLJ90761 fis, clone THYRO1000099 3.68 372.5 -
Identification of a Phosphatidic Acid-Preferring Phospholipase Al
Proc. Nati. Acad. Sci. USA Vol. 91, pp. 9574-9578, September 1994 Biochemistry Identification of a phosphatidic acid-preferring phospholipase Al from bovine brain and testis (lysophosphatidic acld/lysophosphoipase/Triton X-100 miceles/phospholpase D/diacylgycerol kinase) HENRY N. HIGGS AND JOHN A. GLOMSET* Departments of Biochemistry and Medicine and Regional Primate Research Center, Howard Hughes Medical Institute, University of Washington, SL-15, Seattle, WA 98195 Contributed by John A. Glomset, May 31, 1994 ABSTRACT Recent experiments in several laboratories drolysis by phospholipase A (PLA) activities, producing have provided evidence that phosphatidic acid functions in cell lysophosphatidic acid (LPA). A PA-specific PLA2 has been signaling. However, the mechaninsm that regulate cellular reported (16), but detailed information about this enzyme is phosphatidic acid levels remain obscure. Here we describe a lacking. Another possibility is that a PLA1 might metabolize soluble phospholipase Al from bovine testis that preferentially PA to sn-2-LPA. Several PLA1 activities have been identified hydrolyzes phosphatidic acid when assayed in Triton X-100 in mammalian tissues, including one found in rat liver plasma micelles. Moreover, the enzyme hydrolyzes phosphatidic acid membrane (17), another found in rat brain cytosol (18, 19), molecular species containing two unsaturated fatty acids in and others found in lysosomes (20, 21). None of these preference to those containing a combination of saturated and enzymes, however, displays a preference for PA as a sub- unsaturated fatty acyl groups. Under certain conditions, the strate. enzyme also displays lysophospholipase activity toward In the present study, we identify and characterize a cyto- lysophosphatidic acid. The phospholipase Al is not likely to be solic PLA1 with a strong preference for PA. -
Technical Note, Appendix: an Analysis of Blood Processing Methods to Prepare Samples for Genechip® Expression Profiling (Pdf, 1
Appendix 1: Signature genes for different blood cell types. Blood Cell Type Source Probe Set Description Symbol Blood Cell Type Source Probe Set Description Symbol Fraction ID Fraction ID Mono- Lympho- GSK 203547_at CD4 antigen (p55) CD4 Whitney et al. 209813_x_at T cell receptor TRG nuclear cytes gamma locus cells Whitney et al. 209995_s_at T-cell leukemia/ TCL1A Whitney et al. 203104_at colony stimulating CSF1R lymphoma 1A factor 1 receptor, Whitney et al. 210164_at granzyme B GZMB formerly McDonough (granzyme 2, feline sarcoma viral cytotoxic T-lymphocyte- (v-fms) oncogene associated serine homolog esterase 1) Whitney et al. 203290_at major histocompatibility HLA-DQA1 Whitney et al. 210321_at similar to granzyme B CTLA1 complex, class II, (granzyme 2, cytotoxic DQ alpha 1 T-lymphocyte-associated Whitney et al. 203413_at NEL-like 2 (chicken) NELL2 serine esterase 1) Whitney et al. 203828_s_at natural killer cell NK4 (H. sapiens) transcript 4 Whitney et al. 212827_at immunoglobulin heavy IGHM Whitney et al. 203932_at major histocompatibility HLA-DMB constant mu complex, class II, Whitney et al. 212998_x_at major histocompatibility HLA-DQB1 DM beta complex, class II, Whitney et al. 204655_at chemokine (C-C motif) CCL5 DQ beta 1 ligand 5 Whitney et al. 212999_x_at major histocompatibility HLA-DQB Whitney et al. 204661_at CDW52 antigen CDW52 complex, class II, (CAMPATH-1 antigen) DQ beta 1 Whitney et al. 205049_s_at CD79A antigen CD79A Whitney et al. 213193_x_at T cell receptor beta locus TRB (immunoglobulin- Whitney et al. 213425_at Homo sapiens cDNA associated alpha) FLJ11441 fis, clone Whitney et al. 205291_at interleukin 2 receptor, IL2RB HEMBA1001323, beta mRNA sequence Whitney et al.