Activation of necroptosis signaling in cortical neurons in progressive MS
Author(s): ,
C. Picon
R. James
Imperial College London, London, United Kingdom
S. Husein
Imperial College London, London, United Kingdom
N. Mazarakis
Imperial College London, London, United Kingdom
R. Reynolds
Imperial College London, London, United Kingdom
ECTRIMS Online Library. Picón C.
Oct 12, 2018; 228896
Carmen Picón
Carmen Picón
Login now to access Regular content available to all registered users.

You may also access this content "anytime, anywhere" with the Free MULTILEARNING App for iOS and Android
Discussion Forum (0)
Rate & Comment (0)

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

Code of conduct/disclaimer available in General Terms & Conditions
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.

Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.

Google Analytics is used for user behavior tracking/reporting. Google Analytics works in parallel and independently from MLG’s features. Google Analytics relies on cookies and these cookies can be used by Google to track users across different platforms/services.

Save Settings