Proteomics of a conundrum: Thoughts on addressing the aetiology versus progression of multiple sclerosis

Partridge, Melissa A.; Myers, Simon J.; Gopinath, Sumana; Coorssen, Jens R.

doi:10.1002/prca.201400141

Cited by 8 publications

(8 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the lack of clear concept for the aetiology of multiple sclerosis, clinical treatment strategies are limited to delaying progression of the disease by suppressing inflammation [27]. Recently, proteomic analysis of CPZ treated mice's brain samples was suggested as a potentially useful approach for finding therapeutic targets enabling causal treatment of the disease [28]. However, none of the previous studies [10][11][12] targeted the corpus callosum, where CPZinduces the most pronounced demyelination [13].…”

Section: Discussionmentioning

confidence: 99%

Proteomic changes during experimental de- and remyelination in the corpus callosum

et al. 2020

View full text Add to dashboard Cite

Background In the cuprizone model of multiple sclerosis, de-and remyelination can be studied without major interference from the adaptive immune responses. Since previous proteomic studies did not focus on the corpus callosum, where cuprizone causes the most pronounced demyelination, we performed a bottom up proteomic analysis on this brain region. Methods Eight week-old mice treated with 0.2% cuprizone, for 4 weeks and controls (C) were sacrificed after termination of the treatment (4wD), and 2 (2dR) or 14 (2wR) days later. Homogenates of dissected corpus callosum were analysed by quantitative proteomics. For data processing, clustering, gene ontology analysis, and regulatory network prediction, we used Perseus, PANTHER and Ingenuity Pathway Analysis softwares, respectively. Results We identified 4886 unmodified, single-or multi phosphorylated and/or gycosylated (PTM) proteins. Out of them, 191 proteins were differentially regulated in at least one experimental group. We found 57 proteins specific for demyelination, 27 for early-and 57 for late remyelinationwhile 36 proteins were affected in two, and 23 proteins in all three groups. Phosphorylation represented 92% of the post translational modifications among differentially regulated modified (PTM) proteins with decreased level, while it was only 30% of the PTM proteins with increased level. Gene ontology analysis could not classify the demyelination specific proteins into any biological process category, while allocated the remyelination specific ones to nervous system development and myelination as the most specific subcategory. We also identified a protein network in experimental remyelination, and the gene

show abstract

Section: Discussionmentioning

confidence: 99%

Proteomic changes during experimental de- and remyelination in the corpus callosum

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Currently, there are two competing theories regarding the pathophysiology underlying the initiation of Multiple Sclerosis (MS): ’outside-in‘ and ‘inside-out’ [1,2,3,4]. The former proposes that a dysregulated peripheral immune system leads to an autoimmune response against myelin components of the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

Sen

Almuslehi

Gyengési

et al. 2019

Cells

106

View full text Add to dashboard Cite

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

show abstract

“…Multiple Sclerosis (MS) is a heterogeneous, inflammatory demyelinating disease of the human central nervous system (CNS) for which the early initiating events and thus underlying etiology remain unclear (Stys et al, 2012;Stys, 2013;Partridge et al, 2015). Currently, there are no effective treatments to prevent disease initiation and progression (Sriram and Steiner, 2005;Vargas and Tyor, 2017).…”

Section: Introductionmentioning

confidence: 99%

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

Almuslehi

Sen

Shortland

et al. 2020

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration (Cx) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, Cx prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact (Gi) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining Cx with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8 + T-cell recruitment into the CNS. The increased CD8 + T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to Gi female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to Gi males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of Cx+0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an "inside-out" immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS.

show abstract

Proteomics of a conundrum: Thoughts on addressing the aetiology versus progression of multiple sclerosis

Cited by 8 publications

References 47 publications

Proteomic changes during experimental de- and remyelination in the corpus callosum

Proteomic changes during experimental de- and remyelination in the corpus callosum

Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

Contact Info

Product

Resources

About