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

Nellie A Martin, Arkadiusz Nawrocki, Viktor Molnar, Maria L Elkjaer, Eva K Thygesen, Miklos Palkovits, Peter Acs, Tobias Sejbaek, Helle H Nielsen, Zoltan Hegedus, Finn Sellebjerg, Tihamer Molnar, Eudes G V Barbosa, Nicolas Alcaraz, Ferenc Gallyas, Asa F Svenningsen, Jan Baumbach, Hans Lassmann, Martin R Larsen, Zsolt Illes

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Resumé

OBJECTIVE: Here, we applied a multi-omics approach (i) to examine molecular pathways related to de- and remyelination in multiple sclerosis (MS) lesions; and (ii) to translate these findings to the CSF proteome in order to identify molecules that are differentially expressed among MS subtypes.

METHODS: To relate differentially expressed genes in MS lesions to de- and remyelination, we compared transcriptome of MS lesions to transcriptome of cuprizone (CPZ)-induced de- and remyelination. Protein products of the overlapping orthologous genes were measured within the CSF by quantitative proteomics, parallel reaction monitoring (PRM). Differentially regulated proteins were correlated with molecular markers of inflammation by using MesoScale multiplex immunoassay. Expression kinetics of differentially regulated orthologous genes and proteins were examined in the CPZ model.

RESULTS: In the demyelinated and remyelinated corpus callosum, we detected 1239 differentially expressed genes; 91 orthologues were also differentially expressed in MS lesions. Pathway analysis of these orthologues suggested that the TYROBP (DAP12)-TREM2 pathway, TNF-receptor 1, CYBA and the proteasome subunit PSMB9 were related to de- and remyelination. We designed 129 peptides representing 51 orthologous proteins, measured them by PRM in 97 individual CSF, and compared their levels between relapsing (n = 40) and progressive MS (n = 57). Four proteins were differentially regulated among relapsing and progressive MS: tyrosine protein kinase receptor UFO (UFO), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). The orthologous genes/proteins in the mouse brain peaked during acute remyelination. UFO, TIMP-1 and B2M levels correlated inversely with inflammation in the CSF (IL-6, MCP-1/CCL2, TARC/CCL17). APOC2 showed positive correlation with IL-2, IL-16 and eotaxin-3/CCL26.

CONCLUSIONS: Pathology-based multi-omics identified four CSF markers that were differentially expressed in MS subtypes. Upregulated TIMP-1, UFO and B2M orthologues in relapsing MS were associated with reduced inflammation and reflected reparatory processes, in contrast to the upregulated orthologue APOC2 in progressive MS that reflected changes in lipid metabolism associated with increased inflammation.

OriginalsprogEngelsk
Artikelnummere0202530
TidsskriftPLOS ONE
Vol/bind13
Udgave nummer8
Sider (fra-til)1-26
ISSN1932-6203
DOI
StatusUdgivet - 2018

Fingeraftryk

sclerosis
Demyelinating Diseases
Proteome
proteome
beta 2-Microglobulin
Tissue Inhibitor of Metalloproteinase-1
Cuprizone
Apolipoprotein C-II
Proteins
proteins
Genes
lesions (animal)
inflammation
Interleukin-16
Transcriptome
genes
transcriptome
Monitoring
Tumor Necrosis Factor Receptors
Receptor Protein-Tyrosine Kinases

Citer dette

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. / Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes. I: PLOS ONE. 2018 ; Bind 13, Nr. 8. s. 1-26.
@article{6d0f299046c542bc9c2c2e11d1d7723f,
title = "Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes",
abstract = "OBJECTIVE: Here, we applied a multi-omics approach (i) to examine molecular pathways related to de- and remyelination in multiple sclerosis (MS) lesions; and (ii) to translate these findings to the CSF proteome in order to identify molecules that are differentially expressed among MS subtypes.METHODS: To relate differentially expressed genes in MS lesions to de- and remyelination, we compared transcriptome of MS lesions to transcriptome of cuprizone (CPZ)-induced de- and remyelination. Protein products of the overlapping orthologous genes were measured within the CSF by quantitative proteomics, parallel reaction monitoring (PRM). Differentially regulated proteins were correlated with molecular markers of inflammation by using MesoScale multiplex immunoassay. Expression kinetics of differentially regulated orthologous genes and proteins were examined in the CPZ model.RESULTS: In the demyelinated and remyelinated corpus callosum, we detected 1239 differentially expressed genes; 91 orthologues were also differentially expressed in MS lesions. Pathway analysis of these orthologues suggested that the TYROBP (DAP12)-TREM2 pathway, TNF-receptor 1, CYBA and the proteasome subunit PSMB9 were related to de- and remyelination. We designed 129 peptides representing 51 orthologous proteins, measured them by PRM in 97 individual CSF, and compared their levels between relapsing (n = 40) and progressive MS (n = 57). Four proteins were differentially regulated among relapsing and progressive MS: tyrosine protein kinase receptor UFO (UFO), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). The orthologous genes/proteins in the mouse brain peaked during acute remyelination. UFO, TIMP-1 and B2M levels correlated inversely with inflammation in the CSF (IL-6, MCP-1/CCL2, TARC/CCL17). APOC2 showed positive correlation with IL-2, IL-16 and eotaxin-3/CCL26.CONCLUSIONS: Pathology-based multi-omics identified four CSF markers that were differentially expressed in MS subtypes. Upregulated TIMP-1, UFO and B2M orthologues in relapsing MS were associated with reduced inflammation and reflected reparatory processes, in contrast to the upregulated orthologue APOC2 in progressive MS that reflected changes in lipid metabolism associated with increased inflammation.",
author = "Martin, {Nellie A} and Arkadiusz Nawrocki and Viktor Molnar and Elkjaer, {Maria L} and Thygesen, {Eva K} and Miklos Palkovits and Peter Acs and Tobias Sejbaek and Nielsen, {Helle H} and Zoltan Hegedus and Finn Sellebjerg and Tihamer Molnar and Barbosa, {Eudes G V} and Nicolas Alcaraz and Ferenc Gallyas and Svenningsen, {Asa F} and Jan Baumbach and Hans Lassmann and Larsen, {Martin R} and Zsolt Illes",
year = "2018",
doi = "10.1371/journal.pone.0202530",
language = "English",
volume = "13",
pages = "1--26",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

Martin, NA, Nawrocki, A, Molnar, V, Elkjaer, ML, Thygesen, EK, Palkovits, M, Acs, P, Sejbaek, T, Nielsen, HH, Hegedus, Z, Sellebjerg, F, Molnar, T, Barbosa, EGV, Alcaraz, N, Gallyas, F, Svenningsen, AF, Baumbach, J, Lassmann, H, Larsen, MR & Illes, Z 2018, 'Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes', PLOS ONE, bind 13, nr. 8, e0202530, s. 1-26. https://doi.org/10.1371/journal.pone.0202530

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.

I: PLOS ONE, Bind 13, Nr. 8, e0202530, 2018, s. 1-26.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes

AU - Martin, Nellie A

AU - Nawrocki, Arkadiusz

AU - Molnar, Viktor

AU - Elkjaer, Maria L

AU - Thygesen, Eva K

AU - Palkovits, Miklos

AU - Acs, Peter

AU - Sejbaek, Tobias

AU - Nielsen, Helle H

AU - Hegedus, Zoltan

AU - Sellebjerg, Finn

AU - Molnar, Tihamer

AU - Barbosa, Eudes G V

AU - Alcaraz, Nicolas

AU - Gallyas, Ferenc

AU - Svenningsen, Asa F

AU - Baumbach, Jan

AU - Lassmann, Hans

AU - Larsen, Martin R

AU - Illes, Zsolt

PY - 2018

Y1 - 2018

N2 - OBJECTIVE: Here, we applied a multi-omics approach (i) to examine molecular pathways related to de- and remyelination in multiple sclerosis (MS) lesions; and (ii) to translate these findings to the CSF proteome in order to identify molecules that are differentially expressed among MS subtypes.METHODS: To relate differentially expressed genes in MS lesions to de- and remyelination, we compared transcriptome of MS lesions to transcriptome of cuprizone (CPZ)-induced de- and remyelination. Protein products of the overlapping orthologous genes were measured within the CSF by quantitative proteomics, parallel reaction monitoring (PRM). Differentially regulated proteins were correlated with molecular markers of inflammation by using MesoScale multiplex immunoassay. Expression kinetics of differentially regulated orthologous genes and proteins were examined in the CPZ model.RESULTS: In the demyelinated and remyelinated corpus callosum, we detected 1239 differentially expressed genes; 91 orthologues were also differentially expressed in MS lesions. Pathway analysis of these orthologues suggested that the TYROBP (DAP12)-TREM2 pathway, TNF-receptor 1, CYBA and the proteasome subunit PSMB9 were related to de- and remyelination. We designed 129 peptides representing 51 orthologous proteins, measured them by PRM in 97 individual CSF, and compared their levels between relapsing (n = 40) and progressive MS (n = 57). Four proteins were differentially regulated among relapsing and progressive MS: tyrosine protein kinase receptor UFO (UFO), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). The orthologous genes/proteins in the mouse brain peaked during acute remyelination. UFO, TIMP-1 and B2M levels correlated inversely with inflammation in the CSF (IL-6, MCP-1/CCL2, TARC/CCL17). APOC2 showed positive correlation with IL-2, IL-16 and eotaxin-3/CCL26.CONCLUSIONS: Pathology-based multi-omics identified four CSF markers that were differentially expressed in MS subtypes. Upregulated TIMP-1, UFO and B2M orthologues in relapsing MS were associated with reduced inflammation and reflected reparatory processes, in contrast to the upregulated orthologue APOC2 in progressive MS that reflected changes in lipid metabolism associated with increased inflammation.

AB - OBJECTIVE: Here, we applied a multi-omics approach (i) to examine molecular pathways related to de- and remyelination in multiple sclerosis (MS) lesions; and (ii) to translate these findings to the CSF proteome in order to identify molecules that are differentially expressed among MS subtypes.METHODS: To relate differentially expressed genes in MS lesions to de- and remyelination, we compared transcriptome of MS lesions to transcriptome of cuprizone (CPZ)-induced de- and remyelination. Protein products of the overlapping orthologous genes were measured within the CSF by quantitative proteomics, parallel reaction monitoring (PRM). Differentially regulated proteins were correlated with molecular markers of inflammation by using MesoScale multiplex immunoassay. Expression kinetics of differentially regulated orthologous genes and proteins were examined in the CPZ model.RESULTS: In the demyelinated and remyelinated corpus callosum, we detected 1239 differentially expressed genes; 91 orthologues were also differentially expressed in MS lesions. Pathway analysis of these orthologues suggested that the TYROBP (DAP12)-TREM2 pathway, TNF-receptor 1, CYBA and the proteasome subunit PSMB9 were related to de- and remyelination. We designed 129 peptides representing 51 orthologous proteins, measured them by PRM in 97 individual CSF, and compared their levels between relapsing (n = 40) and progressive MS (n = 57). Four proteins were differentially regulated among relapsing and progressive MS: tyrosine protein kinase receptor UFO (UFO), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). The orthologous genes/proteins in the mouse brain peaked during acute remyelination. UFO, TIMP-1 and B2M levels correlated inversely with inflammation in the CSF (IL-6, MCP-1/CCL2, TARC/CCL17). APOC2 showed positive correlation with IL-2, IL-16 and eotaxin-3/CCL26.CONCLUSIONS: Pathology-based multi-omics identified four CSF markers that were differentially expressed in MS subtypes. Upregulated TIMP-1, UFO and B2M orthologues in relapsing MS were associated with reduced inflammation and reflected reparatory processes, in contrast to the upregulated orthologue APOC2 in progressive MS that reflected changes in lipid metabolism associated with increased inflammation.

U2 - 10.1371/journal.pone.0202530

DO - 10.1371/journal.pone.0202530

M3 - Journal article

VL - 13

SP - 1

EP - 26

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 8

M1 - e0202530

ER -