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Activation of necroptosis signaling in cortical neurons in progressive MS
Author(s): ,
C. Picon
Affiliations:
Medicine
,
R. James
Affiliations:
Imperial College London, London, United Kingdom
,
S. Husein
Affiliations:
Imperial College London, London, United Kingdom
,
N. Mazarakis
Affiliations:
Imperial College London, London, United Kingdom
R. Reynolds
Affiliations:
Imperial College London, London, United Kingdom
ECTRIMS Online Library. Picón C.
Oct 12, 2018; 228896
Carmen Picón
Carmen Picón
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Abstract: P1055

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Pathology

Introduction: The progressive phase of multiple sclerosis (SPMS) is associated with the presence of extensive subpial grey matter lesions (GMLs) with significant neuronal loss and the presence of inflammatory infiltrates in the subarachnoid space.
Aim: We investigated the hypothesis that molecules produced in the meninges diffuse to the underlying GM leading to molecular hallmarks of GM pathology. We focused on the role of tumour necrosis factor (TNF) signaling, which is known to be increased in SPMS.
Methods: We analyzed the molecules of interest by western blot and IHC in the grey matter of 40 SPMS and 10 controls. We injected lentiviral vectors carrying the TNF and interferon-gamma genes into the subarachnoid space of DA rats.
Results: TNF-receptor 1 (TNFR-1) was significantly up-regulated in SPMS compared to controls, while no differences were found in the expression levels of TNFR2. SPMS cases also showed a dramatic down-regulation of two key proteins involved in the apoptosis signaling pathway, CYLD and the cleaved active from of caspase 8. In contrast, MS cases showed a significant increase in the key proteins of the necroptotic pathway, phospho-RIPK3 and phospho-MLKL (p-MLKL), which was associated with the level of meningeal inflammation. Hence, we investigated the oligomerization of MLKL, a sign of activated necroptosis. MLKL trimers were only found in the GM of SPMS cases. Interestingly, we observed RIPK3 and MLKL and their phosphorylated forms mainly localised in neurons in the grey matter. The density of neurons expressing p-MLKL was significantly increased in MS cases compared to controls. p-MLKL was found to be localised primarily to the nucleus, which was verified by nuclear protein extraction. Additionally, we investigated whether the presence of p-MLKL was associated with the activation of other markers of cell death and found that only MS cases expressing high levels p-MLKL also expressed the cleaved form of PARP-1. Finally, persistent cytokine production over 1 month in DA rats produced chronic inflammation in the meninges and increased levels of the necroptosis markers p-MLKL and p-RIPK3 in underlying cortical neurons.
Conclusions: Our data show that in SPMS there is a shift in the balance of TNF dependent signaling pathways towards TNFR1-mediated necroptosis in cortical neurons, which could be responsible for the neurodegeneration observed in the grey matter of MS patients.
Disclosure: Carmen: Nothing to disclose

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