Imperial College London
Alternate

Professor Richard Reynolds, BSc AKC PhD

Faculty of Medicine, Department of Brain Sciences

Professor of Cellular Neurobiology
 
 
 
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Contact

 

+44 (0)20 7594 6668r.reynolds

 
 
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Location

 

E414Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Picon:2021:10.1007/s00401-021-02274-7,
author = {Picon, C and Jayaraman, A and James, R and Beck, C and Gallego, P and Witte, ME and van, Horssen J and Mazarakis, ND and Reynolds, R},
doi = {10.1007/s00401-021-02274-7},
journal = {Acta Neuropathologica},
pages = {585--604},
title = {Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter},
url = {http://dx.doi.org/10.1007/s00401-021-02274-7},
volume = {141},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Sustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meni
AU  - Picon,C
AU  - Jayaraman,A
AU  - James,R
AU  - Beck,C
AU  - Gallego,P
AU  - Witte,ME
AU  - van,Horssen J
AU  - Mazarakis,ND
AU  - Reynolds,R
DO  - 10.1007/s00401-021-02274-7
EP  - 604
PY  - 2021///
SN  - 0001-6322
SP  - 585
TI  - Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter
T2  - Acta Neuropathologica
UR  - http://dx.doi.org/10.1007/s00401-021-02274-7
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000616740600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://link.springer.com/article/10.1007%2Fs00401-021-02274-7
UR  - http://hdl.handle.net/10044/1/88136
VL  - 141
ER  -
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