LC-MS/MS glycomics of idiopathic rapid eye movement sleep behavior disorder

Xue Dong, Stefania Mondello, Firas Kobeissy, Farid Talih, Raffaele Ferri, Yehia Mechref, Xue Dong, Stefania Mondello, Firas Kobeissy, Farid Talih, Raffaele Ferri, Yehia Mechref

Abstract

Idiopathic REM sleep behavior disorder (iRBD) is now considered a prodromal stage of an α-synucleinopathy-related to neurodegenerative disease such as Parkinson's diseases. Emerging evidence has shown that post-translational modification or glycosylation are implicated in dynamic disease mechanisms and the onset of many pathological conditions. We hypothesized that the characterization of the glycosylation pattern of patients with RBD would be of great value to understand the pathophysiology and underlying mechanisms and represent potentially useful biomarkers for disease-associated molecular changes. To test this hypothesis, we assessed the serum glycome of patients with RBD and compared to that of healthy controls. NanoRPLC-MS was used to generate quantitative N-glycan profiles while high-temperature PGC-LC-MS platform was employed to generate quantitative isomeric N-glycan profiles. By analyzing permethylated glycans derived from human blood sera on C18-LC-MS/MS, we identified 59 N-glycan structures in healthy (control) cohort, 56 N-glycans in RBD cohort. Sixteen N-glycans structures were found to be significantly altered in the RBD cohort (p < 0.05). N-glycans with the composition of HexNAc4 Hex5 Fuc1 , HexNAc5 Hex5 , and HexNAc4 Hex5 Fuc1 NeuAc1 presented the most substantial difference between controls and RBD patients (p < 0.01). HexNAc4 Hex5 Fuc1 NeuAc1 showed a relatively high abundance (3.1 ± 0.7% in the control cohort versus 4 ± 3% in the idiopathic RBD cohort). These N-glycans can be potential diagnostic biomarker candidates and provide a window into underlying neurodegenerative processes in patients with idiopathic RBD. In addition, 7 N-glycan isomers were significantly different between controls and RBD patients (p < 0.05). HexNAc4 Hex5 Fuc1 NeuAc1 (4511-2) and HexNAc4 Hex5 Fuc1 NeuAc2 (4512-2) showed the most substantial difference between the control and idiopathic RBD cohorts (p < 0.001). Levels of both these two isomeric structures were higher in the idiopathic RBD cohort. Further larger studies are required to assess the reproducibility of these findings and to elucidate the role played by the changes in glycan structures in the pathogenetic mechanisms of RBD. This information will be instrumental in developing molecular therapeutic targets to promote neuroprotection and prevention of neurodegeneration.

Keywords: Idiopathic RBD; LC-MS/MS; N-glycans.

Conflict of interest statement

The authors have declared no conflict of interest.

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figures

Figure 1.
Figure 1.
A flowchart summarizing sample preparation and analysis.
Figure 2.
Figure 2.
Extracted Ion Chromatogram (EIC) of permethylated glycans derived from bloodsamples of (a) control and (b) patient with idiopathic RBD. Symbols: , N-acetylglucosamine (GlcNAc); , Galactose (Gal); , Fucose (Fuc); , Mannose (Man); , Glucose (Glc); , N-acetylneuraminic acid (NeuAc/Sialic Acid);
Figure 3.
Figure 3.
Bar graphs of the LC-MS relative abundances of permethylated N-glycan with significant differences (p<0.05) between control and idiopathic RBD cohorts. Symbols: see Figure 2.
Figure 4.
Figure 4.
(a) The PCA plot of total N-glycan profile. (b) The PCA plot of N-glycans with significant difference (p<0.05). (c) The PCA plot of N-glycan isomers. (d) The PCA plot of N-glycan isomers with significant difference (p<0.05).
Figure 5.
Figure 5.
Bar graphs of the LC-MS relative abundances of permethylated N-glycan isomers with significant differences (p<0.05) between control and idiopathic RBD cohorts. Symbols: see Figure 2.

References

    1. Boeve BF, Ann. N. Y. Acad. Sci. 2010, 1184, 15–54.
    1. Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, Sanchez-Valle R, Vilaseca I, Lomeña F, Vilas D, Lladó A, Gaig C, Santamaria J, Lancet Neurol. 2013, 12, 443–453.
    1. Kim S, Park JM, Moon J, Choi HJ, Exp. Neurol. 2014, 252, 63–74.
    1. Mondello S, Kobeissy F, Mechref Y, Zhao J, Talih F, R., , Cosentino F, Antelmi E, Moresco M, Plazzi G, Ferri R, Neurology 2018, In press.
    1. Abd Hamid UM, Royle L, Saldova R, Radcliffe CM, Harvey DJ, Storr SJ, Pardo M, Antrobus R, Chapman CJ, Zitzmann N, Robertson JF, Dwek RA, Rudd PM, Glycobiology 2008, 18, 1105–1118.
    1. Meany DL, Chan DW, Clin. Proteomics 2011, 8, 7.
    1. Wooding KM, Peng W, Mechref Y, Curr. Pharm. Biotechnol. 2016, 17, 788–801.
    1. Veillon L, Huang Y, Peng W, Dong X, Cho BG, Mechref Y, Electrophoresis 2017, 38, 2100–2114.
    1. Goulabchand R, Vincent T, Batteux F, Eliaou JF, Guilpain P, Autoimmun. Rev. 2014, 13, 742–750.
    1. Abou-Abbass H, Abou-El-Hassan H, Bahmad H, Zibara K, Zebian A, Youssef R, Ismail J, Zhu R, Zhou S, Dong X, Nasser M, Bahmad M, Darwish H, Mechref Y, Kobeissy F, Electrophoresis 2016, 37, 1549–1561.
    1. Dong X, Zhou S, Mechref Y, Electrophoresis 2016, 37, 1532–1548.
    1. Kailemia MJ, Ruhaak LR, Lebrilla CB, Amster IJ, Anal. Chem. 2013, 86, 196–212.
    1. Hu Y, Desantos-Garcia JL, Mechref Y, Rapid Commun. Mass Spectrom. 2013, 27, 865–877.
    1. Hu Y, Mechref Y, Electrophoresis 2012, 33, 1768–1777.
    1. Huang Y, Zhou S, Zhu J, Lubman DM, Mechref Y, Electrophoresis 2017, 38, 2160–2167.
    1. Mechref Y, Zhou S, Hu Y, Hussein A, Tang H, Encycl. Anal. Chem. 2014, 10.1002/9780470027318.a9780470029400
    1. Mechref Y, Kang P, Novotny MV, Methods Mol. Biol. 2009, 534, 53–64.
    1. Zhou S, Hu Y, Mechref Y, Electrophoresis 2016, 37, 1506–1513.
    1. Zhou S, Veillon L, Dong X, Huang Y, Mechref Y, Analyst 2017, 142, 4446–4455.
    1. Zhou S, Huang Y, Dong X, Peng W, Veillon L, Kitagawa DAS, Aquino AJA, Mechref Y, Anal. Chem. 2017, 89, 6590–6597.
    1. Zhou S, Dong X, Veillon L, Huang Y, Mechref Y, Anal. Bioanal. Chem. 2017, 409, 453–466.
    1. Sateia MJ, Chest 2014, 146, 1387–1394.
    1. Hu Y, Zhou S, Yu CY, Tang H, Mechref Y, Rapid Commun. Mass Spectrom. 2015, 29, 135–142.
    1. Yu CY, Mayampurath A, Hu Y, Zhou S, Mechref Y, Tang H, Bioinformatics 2013, 29, 1706–1707.
    1. Abou-Abbass H, Bahmad H, Abou-El-Hassan H, Zhu R, Zhou S, Dong X, Hamade E, Mallah K, Zebian A, Ramadan N, Mondello S, Fares J, Comair Y, Atweh S, Darwish H, Zibara K, Mechref Y, Kobeissy F, Electrophoresis 2016, 37, 1562–1576.
    1. Wildburger NC, Zhou S, Zacharias LG, Kroes RA, Moskal JR, Schmidt M, Mirzaei P, Gumin J, Lang FF, Mechref Y, Nilsson CL, J. Proteome Res. 2015, 14, 3932–3939.
    1. Barber TR, Lawton M, Rolinski M, Evetts S, Baig F, Ruffmann C, Gornall A, Klein JC, Lo C, Dennis G, Bandmann O, Quinnell T, Zaiwalla Z, Ben-Shlomo Y, Hu MTM, Sleep 2017, 40.
    1. Zhou J, Zhang J, Li Y, Du L, Li Z, Lei F, Wing YK, Kushida CA, Zhou D, Tang X, Sleep Med. 2015, 16, 414–418.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner