Tumor necrosis factor (TNF) plays a dual role in neurodegenerative diseases. Whereas TNF receptor (TNFR) 1 is predominantly associated with neurodegeneration, TNFR2 is involved in tissue regeneration and neuroprotection. Accordingly, the availability of TNFR2-selective agonists could allow the development of new therapeutic treatments of neurodegenerative diseases. We constructed a soluble, human TNFR2 agonist (TNC-scTNF(R2)) by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which is comprised of three TNF domains connected by short peptide linkers. TNC-scTNF(R2) specifically activated TNFR2 and possessed membrane-TNF mimetic activity, resulting in TNFR2 signaling complex formation and activation of downstream signaling pathways. Protection from neurodegeneration was assessed using the human dopaminergic neuronal cell line LUHMES. First we show that TNC-scTNF(R2) interfered with cell death pathways subsequent to H(2)O(2) exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H(2)O(2) sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNF(R2) rescues neurons after induction of cell death by 6-OHDA. Since TNFR2 is not only promoting anti-apoptotic responses but also plays an important role in tissue regeneration, activation of TNFR2 signaling by TNC-scTNF(R2) appears a promising strategy to ameliorate neurodegenerative processes.
Fischer, Roman
Maier, Olaf
Siegemund, Martin
Wajant, Harald
Scheurich, Peter
Pfizenmaier, Klaus
eng
Research Support, Non-U.S. Gov't
PLoS One. 2011;6(11):e27621. doi: 10.1371/journal.pone.0027621. Epub 2011 Nov 14.
%0 Journal Article
%1 Fischer2011
%A Fischer, Roman
%A Maier, Olaf
%A Siegemund, Martin
%A Wajant, Harald
%A Scheurich, Peter
%A Pfizenmaier, Klaus
%D 2011
%J PLoS ONE
%K 2011 izi pfizenmaier
%N 11
%P e27621
%R 10.1371/journal.pone.0027621
%T A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death
%U https://www.ncbi.nlm.nih.gov/pubmed/22110694
%V 6
%X Tumor necrosis factor (TNF) plays a dual role in neurodegenerative diseases. Whereas TNF receptor (TNFR) 1 is predominantly associated with neurodegeneration, TNFR2 is involved in tissue regeneration and neuroprotection. Accordingly, the availability of TNFR2-selective agonists could allow the development of new therapeutic treatments of neurodegenerative diseases. We constructed a soluble, human TNFR2 agonist (TNC-scTNF(R2)) by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which is comprised of three TNF domains connected by short peptide linkers. TNC-scTNF(R2) specifically activated TNFR2 and possessed membrane-TNF mimetic activity, resulting in TNFR2 signaling complex formation and activation of downstream signaling pathways. Protection from neurodegeneration was assessed using the human dopaminergic neuronal cell line LUHMES. First we show that TNC-scTNF(R2) interfered with cell death pathways subsequent to H(2)O(2) exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H(2)O(2) sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNF(R2) rescues neurons after induction of cell death by 6-OHDA. Since TNFR2 is not only promoting anti-apoptotic responses but also plays an important role in tissue regeneration, activation of TNFR2 signaling by TNC-scTNF(R2) appears a promising strategy to ameliorate neurodegenerative processes.
%Z Fischer, Roman
Maier, Olaf
Siegemund, Martin
Wajant, Harald
Scheurich, Peter
Pfizenmaier, Klaus
eng
Research Support, Non-U.S. Gov't
PLoS One. 2011;6(11):e27621. doi: 10.1371/journal.pone.0027621. Epub 2011 Nov 14.
%7 2011/11/24
%@ 1932-6203
@article{Fischer2011,
abstract = {Tumor necrosis factor (TNF) plays a dual role in neurodegenerative diseases. Whereas TNF receptor (TNFR) 1 is predominantly associated with neurodegeneration, TNFR2 is involved in tissue regeneration and neuroprotection. Accordingly, the availability of TNFR2-selective agonists could allow the development of new therapeutic treatments of neurodegenerative diseases. We constructed a soluble, human TNFR2 agonist (TNC-scTNF(R2)) by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which is comprised of three TNF domains connected by short peptide linkers. TNC-scTNF(R2) specifically activated TNFR2 and possessed membrane-TNF mimetic activity, resulting in TNFR2 signaling complex formation and activation of downstream signaling pathways. Protection from neurodegeneration was assessed using the human dopaminergic neuronal cell line LUHMES. First we show that TNC-scTNF(R2) interfered with cell death pathways subsequent to H(2)O(2) exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H(2)O(2) sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNF(R2) rescues neurons after induction of cell death by 6-OHDA. Since TNFR2 is not only promoting anti-apoptotic responses but also plays an important role in tissue regeneration, activation of TNFR2 signaling by TNC-scTNF(R2) appears a promising strategy to ameliorate neurodegenerative processes.},
added-at = {2018-02-01T14:56:48.000+0100},
annote = {Fischer, Roman
Maier, Olaf
Siegemund, Martin
Wajant, Harald
Scheurich, Peter
Pfizenmaier, Klaus
eng
Research Support, Non-U.S. Gov't
PLoS One. 2011;6(11):e27621. doi: 10.1371/journal.pone.0027621. Epub 2011 Nov 14.},
author = {Fischer, Roman and Maier, Olaf and Siegemund, Martin and Wajant, Harald and Scheurich, Peter and Pfizenmaier, Klaus},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/23d35b256f68387179a616dcbcd5ed549/cristiano},
doi = {10.1371/journal.pone.0027621},
edition = {2011/11/24},
interhash = {d397b09c495bcefb2b6a78d063613bdb},
intrahash = {3d35b256f68387179a616dcbcd5ed549},
isbn = {1932-6203},
issn = {19326203},
journal = {PLoS ONE},
keywords = {2011 izi pfizenmaier},
number = 11,
pages = {e27621},
pmid = {22110694},
timestamp = {2018-07-25T12:32:54.000+0200},
title = {{A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/22110694},
volume = 6,
year = 2011
}