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Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes

Martin, Nellie A., Nawrocki, Arkadiusz, Molnar, Viktor, Elkjaer, Maria L., Thygesen, Eva K., Palkovits, Miklos, Acs, Peter, Sejbaek, Tobias, Nielsen, Helle H., Hegedus, Zoltan, Sellebjerg, Finn, Molnar, Tihamer, Barbosa, Eudes G. V., Alcaraz, Nicolas, Gallyas, Ferenc, Svenningsen, Asa F., Baumbach, Jan, Lassmann, Hans, Larsen, Martin R., Illes, Zsolt·2018·PLOS ONE
DOI 10.1371/journal.pone.0202530PMC PMC6095600
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Fig 1 Outline of the experimental design. The transcriptome of punched out corpus callosum was examined at 4 time points in the cuprizone (CPZ) model: early and full demyelination (2 and 4 week CPZ, DEM), acute remyelination (aREM, 2 days after suspending CPZ) and full remyelination (fREM, 14 days after suspending CPZ) by 4x44K Agilent Whole Mouse Genom Expression Microarray. Differentially expressed genes at 4 week demyelination, acute and full remyelination were then compared to published transcriptomes of MS lesions. The CSF proteome was established by liquid chromatography mass spectrometry (LC-MS/MS) in a discovery MS cohort (cohort 1, altogether 30 samples). Protein products of overlapping orthologous CPZ/MS genes were then screened in this MS-CSF proteome. Next, levels of selected 129 peptides of 51 proteins of orthologous CPZ/MS genes were measured in altogether 97 individual MS samples (cohort 1 and 2) by targeted proteomics (parallel reaction monitoring, PRM), and stratified according to relapsing and progressive MS subtypes. The differentially regulated proteins were correlated with concentration of molecular markers of inflammation and axonal degeneration (neurofilament light chain, NFL) [15] in the MS-CSF. The expression kinetics of orthologous genes and proteins was examined by immunohistochemistry (IHC) in the CPZ model and related to demyelination, acute remyelination and full remyelination.
Fig 1 Outline of the experimental design. The transcriptome of punched out corpus callosum was examined at 4 time points in the cuprizone (CPZ) model: early and full demyelination (2 and 4 week CPZ, DEM), acute remyelination (aREM, 2 days after suspending CPZ) and full remyelination (fREM, 14 days after suspending CPZ) by 4x44K Agilent Whole Mouse Genom Expression Microarray. Differentially expressed genes at 4 week demyelination, acute and full remyelination were then compared to published transcriptomes of MS lesions. The CSF proteome was established by liquid chromatography mass spectrometry (LC-MS/MS) in a discovery MS cohort (cohort 1, altogether 30 samples). Protein products of overlapping orthologous CPZ/MS genes were then screened in this MS-CSF proteome. Next, levels of selected 129 peptides of 51 proteins of orthologous CPZ/MS genes were measured in altogether 97 individual MS samples (cohort 1 and 2) by targeted proteomics (parallel reaction monitoring, PRM), and stratified according to relapsing and progressive MS subtypes. The differentially regulated proteins were correlated with concentration of molecular markers of inflammation and axonal degeneration (neurofilament light chain, NFL) [15] in the MS-CSF. The expression kinetics of orthologous genes and proteins was examined by immunohistochemistry (IHC) in the CPZ model and related to demyelination, acute remyelination and full remyelination.CC BY · PubMed Central
Fig 2 Gene expression during experimental de- and remyelination and orthologous genes in MS lesions. (A) Overlaps of differentially expressed (at least 2-fold change and statistically significant difference at corrected p<0.05) genes in four CPZ-treated experimental conditions compared to the untreated controls are visualized by Venn diagram. Intensity of filling grey colour indicates the relative percent of all genes shown. The transcriptome of demyelination was determined after 2 and 4 weeks of CPZ administration (2-week DEM, 4-week DEM); remyelination transcriptomes were determined 2 days and 14 days after suspending CPZ (acute and full remyelination; 2-day REM, 2-week REM). (B) Orthologous genes in MS and CPZ lesions were determined by comparing differentially expressed genes in white matter and cortical lesions of MS patients and MS susceptibility genes to transcriptome signatures of CPZ-induced demyelination at 2 and 4 weeks (2wD, 4wD), acute remyelination 2 days after suspending CPZ (2dR), and during full remyelination 2 weeks after suspending CPZ (2wR). The heatmaps represent the expression of orthologous: overlapping MS genes during demyelination and remyelination phases of the CPZ model.
Fig 2 Gene expression during experimental de- and remyelination and orthologous genes in MS lesions. (A) Overlaps of differentially expressed (at least 2-fold change and statistically significant difference at corrected p<0.05) genes in four CPZ-treated experimental conditions compared to the untreated controls are visualized by Venn diagram. Intensity of filling grey colour indicates the relative percent of all genes shown. The transcriptome of demyelination was determined after 2 and 4 weeks of CPZ administration (2-week DEM, 4-week DEM); remyelination transcriptomes were determined 2 days and 14 days after suspending CPZ (acute and full remyelination; 2-day REM, 2-week REM). (B) Orthologous genes in MS and CPZ lesions were determined by comparing differentially expressed genes in white matter and cortical lesions of MS patients and MS susceptibility genes to transcriptome signatures of CPZ-induced demyelination at 2 and 4 weeks (2wD, 4wD), acute remyelination 2 days after suspending CPZ (2dR), and during full remyelination 2 weeks after suspending CPZ (2wR). The heatmaps represent the expression of orthologous: overlapping MS genes during demyelination and remyelination phases of the CPZ model.CC BY · PubMed Central
Fig 3 Upstream regulators of up- and down-regulated orthologous genes in the cuprizone model and MS lesions. Upstream regulators of up- and down-regulated orthologous genes were determined by Ingenuity Pathway Analysis. The experimentally observed gene expression tendencies are shown by the bottom line of nodes of the graphs (red increased, green decreased expression), while the networks above these genes displays the predicted regulatory networks might be responsible for the detected transcription effect. Orange color in the regulatory network indicates positive and blue color indicates negative regulatory effects. Marks on the graph edges shows the type of functional interactions (E: expression, LO: localization, A: activation, TR: translocation, T: transcription, RB: regulation of binding, PD: protein-DNA binding, P: phosphorylation) and the number of the supporting evidences in Ingenuity Knowledge Base.
Fig 3 Upstream regulators of up- and down-regulated orthologous genes in the cuprizone model and MS lesions. Upstream regulators of up- and down-regulated orthologous genes were determined by Ingenuity Pathway Analysis. The experimentally observed gene expression tendencies are shown by the bottom line of nodes of the graphs (red increased, green decreased expression), while the networks above these genes displays the predicted regulatory networks might be responsible for the detected transcription effect. Orange color in the regulatory network indicates positive and blue color indicates negative regulatory effects. Marks on the graph edges shows the type of functional interactions (E: expression, LO: localization, A: activation, TR: translocation, T: transcription, RB: regulation of binding, PD: protein-DNA binding, P: phosphorylation) and the number of the supporting evidences in Ingenuity Knowledge Base.CC BY · PubMed Central
Fig 4 Differential regulation of 4 peptides in the CSF of patients with relapsing and progressive MS. Level of peptides relative to the respective stable isotope standard is indicated by scatter plots, and was quantified by targeted proteomics, parallel reaction monitoring in the CSF of patients with relapsing-remitting MS (RRMS, n = 40), secondary progressive MS (SPMS, n = 27), and primary progressive MS (PPMS, n = 30). (ANOVA, corrected for multiple-testing, using Benjamini-Hochberg). See also S1 and S3 Tables.
Fig 4 Differential regulation of 4 peptides in the CSF of patients with relapsing and progressive MS. Level of peptides relative to the respective stable isotope standard is indicated by scatter plots, and was quantified by targeted proteomics, parallel reaction monitoring in the CSF of patients with relapsing-remitting MS (RRMS, n = 40), secondary progressive MS (SPMS, n = 27), and primary progressive MS (PPMS, n = 30). (ANOVA, corrected for multiple-testing, using Benjamini-Hochberg). See also S1 and S3 Tables.CC BY · PubMed Central
Fig 5 Correlation of peptide levels with pro-inflammatory markers in the CSF of patients with relapsing-remitting MS. The concentration of the indicated biomarkers was examined by MesoScale Discovery technique, and the levels of peptides were quantified by parallel reaction monitoring in the CSF of 17 patients with RRMS.
Fig 5 Correlation of peptide levels with pro-inflammatory markers in the CSF of patients with relapsing-remitting MS. The concentration of the indicated biomarkers was examined by MesoScale Discovery technique, and the levels of peptides were quantified by parallel reaction monitoring in the CSF of 17 patients with RRMS.CC BY · PubMed Central
Fig 6 Experimental de- and remyelination kinetics of 4 genes with differentially regulated orthologues in the MS CSF. Relative expression of orthologous mouse genes of the 4 proteins was examined in the corpus callosum of control mice and during different phases of CPZ-induced demyelination (2 weeks, n = 3; and 4 weeks, n = 4), and acute and full remyelination (2 days after suspending CPZ, n = 3; and 14 days after suspending CPZ, n = 3) by 4x44K Agilent Whole Mouse Genom Expression Microarray. Mean of relative expression is shown at these time points.
Fig 6 Experimental de- and remyelination kinetics of 4 genes with differentially regulated orthologues in the MS CSF. Relative expression of orthologous mouse genes of the 4 proteins was examined in the corpus callosum of control mice and during different phases of CPZ-induced demyelination (2 weeks, n = 3; and 4 weeks, n = 4), and acute and full remyelination (2 days after suspending CPZ, n = 3; and 14 days after suspending CPZ, n = 3) by 4x44K Agilent Whole Mouse Genom Expression Microarray. Mean of relative expression is shown at these time points.CC BY · PubMed Central
Fig 7 Expression of differentially regulated orthologous proteins in the CSF of patients with MS during CPZ-induced de- and remyelination. Protein expression of the indicated proteins have been examined by immunohistochemistry in the corpus callosum of controls, 4 weeks after CPZ administration (demyelination), and 2 days after suspending CPZ (acute remyelination). Blank indicates no antibody. Magnification bars represent 100 micrometer.
Fig 7 Expression of differentially regulated orthologous proteins in the CSF of patients with MS during CPZ-induced de- and remyelination. Protein expression of the indicated proteins have been examined by immunohistochemistry in the corpus callosum of controls, 4 weeks after CPZ administration (demyelination), and 2 days after suspending CPZ (acute remyelination). Blank indicates no antibody. Magnification bars represent 100 micrometer.CC BY · PubMed Central

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Metadata

Authors
Martin, N. A., Nawrocki, A., Molnar, V., Elkjaer, M. L., Thygesen, E. K., Palkovits, M., Acs, P., Sejbaek, T., Nielsen, H. H., Hegedus, Z., Sellebjerg, F., Molnar, T., Barbosa, E. G. V., Alcaraz, N., Gallyas, F., Svenningsen, A. F., Baumbach, J., Lassmann, H., Larsen, M. R., & Illes, Z.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-08-16
Volume
13
Issue
8
Pages
e0202530
ISSN
1932-6203
DOI
10.1371/journal.pone.0202530
PMC
PMC6095600
Cited by
29
References
14
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Lundbeckfonden (R118-A11472)
  • Országos Tudományos Kutatási Alapprogramok (OTKA-K77892, OTKA-NN109841)
  • Region Syddanmark (14/24200)
  • Jascha Fonden (5589)
  • Direktør Ejnar Jonasson Kaldet Johnsen og Hustrus Mindelegat (5609)
  • Odense Universitetshospital (A474)
  • Scleroseforeningen (R399-A28099-B15690 and R431-A29926-B15690)
  • GINOP (GINOP 2.3.2-15-2016-00049 and GINOP 2.3.3-15-2016-00025)
  • Fonden for Lægevidenskabensfremme (13-267)
  • Villum Fonden (Young Investigator grant nr. 13154)
  • Nemzeti Kutatási és Technológiai Hivatal (KTIA_NAP_13-1-2013-0001)

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