Mapping and sequencing of gangliosides from anencephaly by electrospray ionization

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Mapping and sequencing of gangliosides from anencephaly by electrospray ionization

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Mapping and sequencing of gangliosides from anencephaly by electrospray ionization

  1. 1. Article lead Auth or: Mosoarca, Cristina Date: 2008Article: 5. Mapping an d Sequencing of Gangliosides from Anencephaly by ElectrosprayIonizati on High Capacity Ion Trap Mass Spectrometry. 1. Pain felt at: a. If the articl e specifically asserts unborn children feel pain, at what post­ fe rtilization age? b. Page: 72, First paragraph. "Infa nts born w ith anencephaly are usually blind, deaf, unco nscious, and unable to fee l pain." 2. Nociceptors: a. Ift he article states nociceptors are present, at what post-fertilization age? b. Page: 3. Tha lamus link: a. Ifthe article states nerves link nociceptors to the thalamus, at what post­ fert ilization age? b. Page: 4. Subcortical plate link: a. If the article states ne rves link to the subcortical plate, at what post-fertilization age? b. Page: 5. Noxious stim uli reaction: a . Does the article refer to reaction to noxious stimuli? At what post-fertilization age? b. Page: 6. Stress hormones: a. Does the article refer to increase in stress hormones with noxious stimuli? At what post-fertilization age? b. Page: 7. Long-term effects: a. Does the article describe long term harmful effects from exposure to noxious sti muli? b. Page: 8. Fetal anesthesia: a. Does the article refer to use of fetal anesthesia and its effect? At what post­ fertilization age? b. Page: 9. Cortex: a. Does the article relate to the asserted need for cortical involvement to experience pain? How?
  2. 2. b. Page: 72, First Paragraph. i I ••• the lack of a functioning cerebrum permanently rules out the possibility of ever gaining consciousness. Reflex actions such as breathing and responses to sound or touch may occur."
  3. 3. ,~ ",ro ~~ @ .... . >. . CL ,0 0 uj 5. MAPPING AND SEQUENCING OF GANGLIOSIDES ::> >. FROM ANENCEPHALY BY ELE CTROSPRAY IONlZATION ..0 "0 mGH CAPACITY ION TRAP MASS SPECTROMETRY ~ 2 e CL Q) 1 2 CRISTINA MOSOARCA , ZELJKA VUKELIC , AND ALINA ..0 >. D. ZAMFIR 1,3 ro E /Mass Spectrometry Laboratory, National Institute for Research and "0 C • Development in Electrochemistry and Condensed Maller, Timisoara, Romania co .c • 2Department ofChem istry and Biochemistry, Faculty ofMedicine, University of "­ • co CL• Zagreb, Croatia 1:? 3 HAurel Vlaicu" University ofArad, Romania :5 ro >. ..0 Q) c: Abstract. Congenital malformation referred to as anencephaly is a neural tube defect that occurs (3 when the cephalic end of the neural tube fails to close, resulting in the absence of a major portion 6 Q) of the brain, skull, and scalp. Infants with this disorder are born without a forebrain-the largest 2 >­ part of the brain consisting mainly of the cerebrum, which is responsible for thinking and coordi­ o nation. Although some individuals with anencephaly may be born with a rudimentary brain stem, e:­ rn the lack of a functioning cerebrum permanently rules out the possibility of ever gaining con­ .0 sciousness. Gangliosides (GGs) are sialylated glycosphingolipids present in the cell plasma :.:J (ij membrane, responsible for the modulation of the cell signal transduction events. GGs act as re­ c: ceptors of interferon, epidermal growth factor, nerve growth factor and are differently expressed .Q iU in various patbological states of central nervous system (CNS) acting as biomarkers of CNS dis­ z orders. In this study a native GG mixture extracted and purified from a histopathoJogically-defined Q) :£ anencephalic fetal brain remnant was analyzed by electrospray ionization high capacity ion trap "­ o mass spectrometry. Structural data upon disease-associated species were collected by multiple c: stage collision-induced dissociation of the molecular ions. As a control a native GG mixture o ~ from a nonnal fetal brain in the same developmental stage was used. Comparative screening and Q) Sequencing revealed the differential expression of theCJGg in aberrant vs. healthy tissue and pro­ 8 vided accurate inforination upon the structure of several anencephaly-associated species. Q) :5 1. Introduction Anencephaly, a severe congenital malformation, is frequently associated with other m alformations not involving the central nervous system. Diagnosis is usually anten­ atal and expectation of life is very short [1,2]. Anencephaly is a cephalic disorder that results from a neural tube defect that occurs when the cephalic (head) end ofthe neural tube fails to close, usually between the 23rd and 26th day of pregnancy, resulting in the absence of a major portion of the br~ skull, and scalp. Infants with this disorder (Figure 1) are born without a forebrain, the largest part of the brain consisting mainly of the cerebral hemispheres (which include the isocortex, which is responsible for higher level cognition, i.e., thinking). C. Popescu et al , (eds.), Applications ofMass Spectrometry in Life Safety. 71 o Spriilger Science + Business Media B.V, 2008
  4. 4. 72 C. MOSOARCA, Z. VUKELIC, AND A. D. ZAMFIR Figure 1. Morphoanatomic structure of an anencephalic fetal head The remaining brain tissue is often exposed - not covered by bone or skin.Infants born with anencephaly are usually blind, deaf, unconscious, and unable tofeel pain. Although some individuals with anencephaly may be born with a rudi­mentary brainstem, which controls autonomic and regulatory function, the lackof a functioning cerebrum pennanently rules out the possibility of ever gainingconsciousness [3]. Reflex actions such as breathing and responses to sound ortouch may occur. The disorder is one of the most common disorders of the fetal central nervoussystem. Anencephaly can often be diagnosed before birth through an ultrasoundexamination. The maternal serum alpha-fetoprotein (AFP screening) and detailedfetal ultrasound [2] can be useful for screening for neural tube defects such asspina bifida or anencephaly. There are many false diagnoses for anencephaly, as itis not a common diagnosis, often confused with exencephaly or microcephaly.Also, sometimes a false prognosis stating that an anencephalic baby can live foryears is given, but this cannot occur because the brain is open, meaning that infec­tion sets in rapidly. The anencephalic brain is also usually very disorganised on acellular level. There is no cure or standard treatment for anencephaly and the prognosisfor affected individuals is poor. Most anencephalic babies do not survive birth,accounting for 55% of non-aborted cases. If the infant is not stillborn, then he orshe will usually die within a few hours or days after birth from cardiorespiratoryarrest. In a1most all cases anencephalic infants are not aggressively resuscitatedsince there is no chance of the infant ever achieving a conscious existence. Instead,the usual clinical practice is to offer hydration, nutrition and comfort measures andto "let nature take its course". Artificial ventilation, surgery (to fiX any co-existingcongenital defects), and drug therapy (such as antibiotics) are usually regardedas futil e efforts. Some clinicians and medical ethicists even view the provision ofnutrition and hydration as medically futile, arguing that euthanasia is morally andclinically appropriate in such cases. In the United States, approximately 1,000 to2,000 babies are born with anencephaly each year. Female babies are more likelyto be affected by the disorder.
  5. 5. MAPPING AND .EQUENCING OF GANGLIOSIDES 73 About 95% of women who leam that they will have an anencephalic baby chooseto have an abortion. The cause of anencephaly is unknown. Neural tube defectsdo not follow direct patterns of heredity [4], and recent animal models indicatinga possible association with deficiencies of the transcription factor 1EAD2 [4].Studies show that a woman who has had one child with a neural tube defect suchas anencepha1y, has about a 3% risk to have another child with a neural tube defect.This risk can be reduced to about 1% if the woman takes high dose (4 mg/day) offolic acid before and during pregnancy. It is known that women taking certainmedication for epilepsy and women with insulin dependent diabetes have a higherchance of having a child witb a neuraJ tube defect. Genetic counseling is usuallyoffered to women at a higher risk of having a child with a neural tube defect todiscuss available testing. Recent studies have shown that the addition of folic acid to the diet of womenof child-bearing age may significantly reduce, although not eliminate, the inci­dence of neural tube defects. Therefore, it is recommended that all women of child­bearing age consume 0.4 mg of foli c acid daily, especially those attempting toconceive or who m ay possibly conceive. It is not advisable to wait until pregnancybas begun, since by the time a woman knows she is pregnant, the critical time forthe formation of a neural tube defect has usually already passed. A physician mayprescribe even higher dosages of folic acid (4 mg/day) for women who have had aprevious pregnancy with a neural tube defect. Gangliosides [5-9] are acid glycosphingolipids widely distributed in mostvertebrate tissues and fluids. They are present in mammalian milk, where they arealmost exclusively associated with the membrane fraction of the fat globule. Inhuman milk, the content and individual distribution of gangliosides changes duringlactation, OD3 being the most abundant ganglioside in colostrum, while in maturemilk GM3 is the major individual species. Gangliosides function as "unintended"target receptors for bacterial adhesion in specific tissues. After oral administration,they can be putative decoys that interfere with pathogenic binding in the intestine,this being the main mechanism by which these compounds can prevent infection.Ganglioside-supplemented infant formula has been reported to modifY the intestinalecology of preterm newborns, increasing the Bifidobacteria content and loweringthat of Escherichia coli. In addition, the influence of dietary gangliosides onseveral parameters related to the development of intestinal immune system, suchas cytokine and intestinal IgA production, has also been described in animalmodels. Recently , the influence of OM3 and GD3 on dendritic cell maturation andeffector functionalities has also been reported, suggesting a role for these milkgangliosides, especially GD3, in modulating the process of oral tolerance duringfirst stages of life. Dietary gangliosides may have an important role in the modificationof intestinal microflora and the promotion of intestinal immunity development inthe neonate, and consequently in the prevention of infections during early infancy. [8]Gangliosides (GGs) are sialylated glycosphiugolipids present in the cell plasmamem brane, responsible for the modulation of the cell signal transduction events.
  6. 6. 74 c. MOSOARCA, Z. VUKELlC. AND A. D. ZAMFIRGGs act as receptors of interferon, epidelmal growth factor, nerve growth factorand are differently expressed in various pathological states of central nervous system(CNS) acting as biomarkers ofCNS disorders [10-17]. In this study a native GG mixture extracted and purified from a hystopatologically­defined anencephalic fetal brain remnant was analyzed by electrospray ionizationhigh capacity ion trap mass spectrometry. Structural data upon disease-associatedspecies were collected by multiple stage collision-induced dissociation of the mole­cular ions. The anencephalic cerebral remnant, as a primitive brain structure, represents amodel to study the ganglioside involvement in induction of aberrant brain deve­lopement. We have chosen human anencephalic brain-like formed structures, as apotentially useful physiological system to study the ganglioside invovement inbrain developement and etiology of brain developmental arrest. H~re we presentthe detailed ganglioside composition and quantification in histologically defmedhuman brain-resembling anencephalic tissue structures in· comparison to respec­tive normal fetal brain regions. A difference in the expression of ganglia-series gangliosides with GMla corewas found between anencephalic and normal fetal brain, with less expression ofGMla and GDIa in anencephaly compared with normal fetal brain, in which thesegangliosides dominate. Small amOlmts of GMI b were detected in fetal brain whereasonJy traces were found in anencephalic brain. Lactosamine-containing ganglia­sides were present in fetal and in anencephalic brain as alpha 2-3 as well as alpha2-6 sialylated nLcOse4Cer structures. A heterogeneous group of neolacta-seriesgangtiosides was expressed in anencephalic brain in both the monosialo- and pre­sumed disialoganglioside range. TIlese findings demonstrate a significant changein ganglioside pattern in anencephaly where the process of cell differentiation andmaturation has been severely disturbed [11]. In anencephalic tissue, GMlb, GDIalpha, nLMl and nLDI were expressed at ahigher rate in relation to nOlmal tissue. It can be demonstrated that the anencephaliccerebral remnant, as a prinlitive brain structure, represents a naturally-occurringmodel to study the ganglioside involvement in induction of aberrant brain devel­opment.2. Materials and Methods2.1. MASS SPECTROMETRYMass spectrometry was performed on a High Capacity Ion Trap Ultra (HCT Ultra,PTM discovery) mass spectrometer from Bruker Daltonics, Bremen, Germany.HCT MS is interfaced to a PC ruJUling the CompassTM 1.2. integrated softwarepackage, which includes the HystarlM 3.2.37 module for instrument controllingand spectrum acquisition, Esquire 6.1. 512 and Data Analysis 3.4.179 modules for
  7. 7. MAPPING AND SEQUENCING OF GANGUOSIDE S 7Sstoring the ion chromatograms and processing the MS data. All mass spectra wereacquired using on-line (- ) microESI infusion.2.2. GANGLIOSIDE SAMPLEThe native mixture of gangliosides from a hystopatologically-defined anencephalicfetal brain remnant (36 g.w.) was extracted and purified as described in detailelsewhere [14,18,1 9]. The GG stock solution at approximately 1 mg/ml was pre­pared by dissolving the dried material in MeOH. For MS analysis, the solutionwas evaporated (dig ital SpeedVac Concentrator SPD 111 V -230, Thermo ElectronCorporation, Milford, MA, USA) and the resulting dry substrate was dissolved inMeOH (HPLC grade, Merck, Darmstadt, Gennany) to the final concentration ofapproximately 20 pmol/~I (calculated for an average molecular weight of 2,000).3. Results and DiscussionsIn the past decade, the studies aiming at determination of GG composition, quan­tity, distribution and cell surface expression were almost exclusively conducted onchromatographic, immunochemical and immunohistochemical methods [18,19];however, the information acquired by these techniques is based merely on com­parisons and, because of the detection boundaries, it is restricted to the majorspecies. Therefore, fast atom bombardment (FAB) mass spectrometry (MS) wasintroduced as the fIrst MS method in human brain GG analysis, and showed itsability to provide closer insights into the expression pattern at nanomolar sensi­ 0tivities [20]. Nowadays, modem protocols for detection and sequencing of different types ofglycospbingolipids (GSLs) including GGs and sulfated G1cA-GSLs, based on eithermatrix assisted laser desorption/ionization (MALDI) MS [21-23] or electrosprayionization (ESI) in combination with different analyzers are available [24-27].TLC-MALDI MS [28-30], liquid chromatography [31] and capillary electrophoresis(CE) E SI MS [32-34] couplings were also developed for efficient separation ofcomplex mixtures followed by direct MS analysis. These innovative methods allowed U)not only detection of individually isolated fractions but also a reproducible mapping ro 3:and MSIMS sequencing of single components in complex tissue extracts that are <D 0:accessible only in very low amounts (pico to attomoles). ro a In earlier w ork, to improve the ESI process, increase the experiment throughput,sensitivity and reproducibility, we have implemented fully automated chip-based c onanoESI MS in glycolipidornics [35,36] and multistage sequencing [37]. ro ·c m ro E
  8. 8. 76 C. MOSOARCA, Z. VUKELIC, AND A. D. ZAMFIR In the present work we applied the novel protocol based on BCT multistagesequencing for strucutral analysis of GG from fetal anencephaJic brain-like residue. Screening of the anencephaly GG mixture indicated the dominance of structuresexhibiting short oligosaccharide chains, with sialylation degree 1 and 2. The mostabundant species are GM3, GMl, GDI and GD2. A notable aspect is that the do­minant structures mono- and disialotetraoses are bearing different cerami de resi­dues and that several structures appear associated to anencephaly. Under optimizedsolution and instrumental conditions, the abundances of the ions corresponding tomono- and disialylated GM and GD components dominate while asialo specieswere not found. We and others [38,39] have demonstrated before that a directcorrelation between ganglioside sialylation degree and brain developmental stageexists. Higher sialylation extent was found specific for incipient developmentalstages. Consequently, this elevated expression of sialylated structures representsa marker of brain development stagnation, which occurs in anencephaly. Addi­tionally, GG chains modified by labile attachments such as Fuc or O-Ac wereearlier reported as associated to the tissue in its later fetal developmental phase[38,39]. Present data render interesting infonnation also from this point of view.While several modified structures were eari ler detected in normal fetal brain, onlytwo O-Ac species exhibiting (d I8:1120:0) and (dI 8:0/22:0) ceramide compositionswere identified in anencephalic remnant. For structural elucidation GMI (d18:1/18:0) detected as singly charged ion atm/z 1544.48 and GD2 (d18:1118:0), singly charged ion at mlz 1,383.00 were sub­mitted to multistage CID MS experiments (Figures 2-5).- • • 8.98.20 1092.12 125320 . 1544.48 • YD 726.80 ... .. 1347.60 • ... - 1282.80 - 1432.00Figure 2. Negative ESI HeT MS2 of the singly charged ion at mlz 1,544.48 corresponding ...to the GMI (d18:1118:0) ganglioside species detected in the GG mixture from anencephalicremnant Assignment of the product ions is according to Ref [40,41]
  9. 9. MAPPING AND SE QUENCING OF GANGLJOSIDES 77 Ga lGlcCer Z1 1. . Z, I. " In t G O~G alN A alto~G Ictotc Qli ctotG tr 668 65 " ; Y ~. Y. Yl:t800 1211 .73600400 B, 1. 0· 1 ,0 i - 1 119 3 T I i i 1025 . 7 ~200 I ! i 3 63 .9 2 52847 i 564 ..415 ! 400 500 600 700 800 900 1000 1100 1200 m/zFigure 3. Negative ESI HCT MS 3 of the singly charged ion at m/z 1,253.82 correspondingto the desialylated GMt fragment ion detected in the MS2 mode Assignment of the productions is according to Ref [40,4 1] NeuAc ~a 3 64 8 16 290 ~ 1253 Y ~ I I I 2~ Gal r alNAC Gall- Glc - Ger 1091 888 726 564 Y 20 /8 1 1 Y1 0 QJ 0 Y 20 a (.J 1179 (f) ~ 5 QJFigure 4. Fragmentation pathway of the GM l a species under low energy CID conditions in a rntb n egative ion mode o .!fl -~
  10. 10. 78 C. MOSOARCA, Z. VUKELIC, AND A. D. ZAMFIR a) -MS2(1383.0). 17.6-18.2min #(452-457) Inlens. 109191.// Y3/ Bla 3000 2000 ~..~, ~ ~.: 888.80 1000 , . I. ~ """" . ... 564 .68 . 726 .75 1184.93 o I , , I , , I I I • , , , I I I 250 500 1000 b) -MS3(1383.0->1092.0). 18.7-19.3min #(461-465) Intens. Y 2/ 8 2(; ~•.~ 888.80 .......··/ 250 •..• "" "" •. 200 564 .65 150 . X271fl Y3 ,L I 100 " 708.63 726.80 50 283.03 1152.02 0 t I , I I I I 250 500 750 1250 m/z c) In tens . -MS4(1383 . 0->1092 . 0~888 . 8). 20.1-21.0min #(470-475) Y o ..,-...... -. 564 .62ro .._ Yl .....- 15 726.83" ?2 Zl ! i 10 ! ! : 870.85 81 708.60 5 283.25~ 553.09 336.43 o I I I I 250 500 750 1000 rnlz Figure 5. Negative ESI HCT multistage CID MS of the singly charged ion at mlz 1,383.00 corresponding to the GD2 (d18:1118:0) ganglioside species detected in the GG mixture from anencepbalic remnant: (a) MS2; (b) MS 3 ; (c) MS4 Assignment of the product ions is according to R ef [40,41]
  11. 11. MAPPING AND SEQUENCING F GANGLlOSIDES 79 " ."4. C onclusionsWe developed here a novel strategy in glycolipidomics based on electrospraysample infusion followed by MS detection and multistage sequencing of ganglio­side components in a native mixture extracted from anencephalic fetal brain. ESI MS screening of the native GG mixture from anencephalic fetal brain rem­nant revealed a series of structures exhibiting shorter oligosaccharide chains ascompared to healthy controls in the same developmental stage. GMI and GD2 werefound as dominant structures, a feature which is in agreement with the data collec­ted by thin layer chromatography and immunochemical analyses. Data upon these disease-associated species, obtained by multiple stage collision­induced dissociation of the molecular ions, indicated the structures of the sugarchains as well as the composition of the ceramide moieties. Moreover, the presenceof the GMla structural isomer could be discovered by this method.Applied gallg!ioside nomenclatureGangliosides and the precursor glycosphingolipids are abbreviated according tothe system introduced by Svennerholm in 1980 [42] and the recommendations ofIUPAC-TIJB Commission on Biochemical Nomenclature [43] as follows: LacCer,Galf34G1cP1 Cer; GA2, Gg 3 Cer, GalNAcp4Galp4Gfcf31Cer; GAl, Gg4 Cer,Gal p3GalNAcj34Galp4Glcp1Cer; nLc4Cer, Galp4GlcNAcp3Galp4Glcp1Cer;LC4Cer, Galf33G1cNAcp3Galp4Glcp 1Cer; GM3, n3 -a -Neu5Ac-LacCer; GD3, nJ_a-(Neu5Ach-LacCer; GT3, IIJ-a-(Neu5Ac)rLacCer; GM2, n 3-a-Neu5Ac­Gg3 Cer; GD2, n J-o.-(Neu5Ac)rGg3Cer; GM1a or GM1, n3-o.-Neu5Ac-G~Cer;GMlb, IV3-a-Neu5Ac-Gg 4 Cer; GalNAc-GMlb, rv 3-o.-Neu5Ac-Gg sCer; GDla,IV3-a-NeuSAc,ll3-0.-Neu5Ac-Gg 4Cer; GDI b, II3-o.-(Neu5Ac h-Gg4Cer; GT1 b, 3 . 3 3IV -a-N eu5Ac,ll -o.-(Neu5Ac)r G~Cer; GQl b, ]V -o.-(Neu5Ach,n -o.-(Neu5Ach­Gg 4Cer; nLMl or 3-nLM1, rv3-o.-Neu5Ac-nLc4Cer; LMI of 3-isoLM1, ]V3_o.­Neu5Ac-Lc4Cer; nLD1, disialo-nLc 4CerAcknowledgem ents en m 3 Q)1his work was supported by the Romanian National Authority for Scientific Re­ 0: msearch through the projects CEx. 14/2005, 98/2006 and 11112006 and the Croatian 0. (J)Ministry of Science and Technology under the project no. 108120/20 .
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