A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death

• Published in: PloS one 2011-11, Vol.6 (11), p.e27621
• Main Authors: Fischer, Roman, Maier, Olaf, Siegemund, Martin, Wajant, Harald, Scheurich, Peter, Pfizenmaier, Klaus
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; AKT protein; Alzheimer's disease; Alzheimers disease; Animals; Apoptosis; Biochemistry; Biological activity; Biology; Cell death; Cell Death - drug effects; Cell Differentiation - drug effects; Chromatography; Complex formation; Dopamine; Dopamine receptors; Dopaminergic Neurons - cytology; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Downstream effects; Enzymes; Gene Expression Regulation - drug effects; Genetic engineering; Health aspects; HEK293 Cells; Homeostasis; Humans; Hydrogen peroxide; Hypotheses; Immunology; Internal medicine; Medical treatment; Medicine; Mice; Mortality; Movement disorders; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - pharmacology; Neurosciences; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Parkinson disease; Parkinson's disease; Parkinsons disease; Pathogenesis; Pathways; Peptides; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Tumor Necrosis Factor, Type II - agonists; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - pharmacology; Regeneration; Restoration; Signal transduction; Signal Transduction - drug effects; Signaling; Solubility; Substrate Specificity; Superoxides - pharmacology; Tenascin; Tenascin - chemistry; Tenascin - pharmacology; Tenascin C; Tissue engineering; Trends; Tumor necrosis factor; Tumor necrosis factor receptors; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027621

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.