title: Identification of protein networks involved in the disease course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.
abstract: A more detailed insight into disease mechanisms of multiple sclerosis (MS) is crucial for the development of new and more effective therapies. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins involved in the development of inflammatory brain lesions, to help unravel underlying disease processes. Brainstem proteins were obtained from rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE), a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D-DIGE) followed by mass spectrometry. We identified 75 unique proteins in 92 spots with a significant abundance difference between the experimental groups. To find disease-related networks, these regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA). The analysis revealed that 70% of these proteins have been described to take part in neurological disease. Furthermore, some focus networks were created by IPA. These networks suggest an integrated regulation of the identified proteins with the addition of some putative regulators. Post-synaptic density protein 95 (DLG4), a key player in neuronal signalling and calcium-activated potassium channel alpha 1 (KCNMA1), involved in neurotransmitter release, are 2 putative regulators connecting 64% of the identified proteins. Functional blocking of the KCNMA1 in macrophages was able to alter myelin phagocytosis, a disease mechanism highly involved in EAE and MS pathology. Quantitative analysis of differentially expressed brainstem proteins in an animal model of MS is a first step to identify disease-associated proteins and networks that warrant further research to study their actual contribution to disease pathology.
authors.affiliation: Biomedical Research Institute, Hasselt University and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Vanheel
authors.forename: Ruth
authors.initials: R
authors.lastname: Daniels
authors.forename: Stéphane
authors.initials: S
authors.lastname: Plaisance
authors.forename: Kurt
authors.initials: K
authors.lastname: Baeten
authors.forename: Jerome J A
authors.initials: JJ
authors.lastname: Hendriks
authors.forename: Pierre
authors.initials: P
authors.lastname: Leprince
authors.forename: Debora
authors.initials: D
authors.lastname: Dumont
authors.forename: Johan
authors.initials: J
authors.lastname: Robben
authors.forename: Bert
authors.initials: B
authors.lastname: Brône
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Noben
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism*; D025341:Principal Component Analysis; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D020543:Proteome; D040901:Proteomics / Q000379:methods; D051381:Rats; D011917:Rats, Inbred Lew; D015203:Reproducibility of Results
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008565:Membrane Proteins; D020543:Proteome