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-scTNFR2) 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-scTNFR2 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-scTNFR2 interfered with cell death pathways subsequent to H2O2 exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H2O2 sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNFR2 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-scTNFR2 appears a promising strategy to ameliorate neurodegenerative processes.
Highlights
Tumor necrosis factor (TNF), plays a dominant role in the initiation and perpetuation of chronic inflammation [1], a condition that can lead to a variety of diseases
After verifying selective human TNFR2 activation we evaluated the neuroprotective effect of tenascin C (TNC)-scTNFR2 on LUHMES cells, an established neuronal precursor cell line that has retained the potential of neuronal differentiation into a dopaminergic phenotype [17,18,19,20]
Here we describe a human TNFR2-selective TNF ligand with membrane-bound TNF (memTNF)-mimetic activity (TNC-scTNFR2) that rescues differentiated neurons from cell death post insultem, i.e. under conditions that reflect the time span of a potential therapeutic intervention, for example to limit ischemic lesions after stroke
Summary
Tumor necrosis factor (TNF), plays a dominant role in the initiation and perpetuation of chronic inflammation [1], a condition that can lead to a variety of diseases. Chronic inflammation is a common feature of neurodegenerative diseases of the central nervous system, such as Alzheimer’s disease, Parkinson’s disease (PD) and multiple sclerosis (MS), too [4], and TNF signaling has been implicated as an important factor for the onset of demyelinating diseases. The dual role of TNF in the CNS has been investigated in various mouse models, revealing significant beneficial effects predominantly mediated by TNF receptor (TNFR) 2, whereas TNFR1, directly and indirectly promotes neurotoxicity [2,6]. TNF remains a primary therapeutic target for the treatment of neuroimmune diseases, but therapeutic interference should be strictly receptor selective
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