Tumor Necrosis Factor-α (TNF-α) regulates shedding of TNF-α receptor 1 by the metalloprotease-disintegrin ADAM8: evidence for a protease-regulated feedback loop in neuroprotection
Article
Bartsch, J., Wildeboer, D., Koller, G., Naus, S., Rittger, A., Moss, M., Minai, Y. and Jockusch, H. 2010. Tumor Necrosis Factor-α (TNF-α) regulates shedding of TNF-α receptor 1 by the metalloprotease-disintegrin ADAM8: evidence for a protease-regulated feedback loop in neuroprotection. Journal of Neuroscience. 30 (36), pp. 12210-12218. https://doi.org/10.1523/JNEUROSCI.1520-10.2010
Type | Article |
---|---|
Title | Tumor Necrosis Factor-α (TNF-α) regulates shedding of TNF-α receptor 1 by the metalloprotease-disintegrin ADAM8: evidence for a protease-regulated feedback loop in neuroprotection |
Authors | Bartsch, J., Wildeboer, D., Koller, G., Naus, S., Rittger, A., Moss, M., Minai, Y. and Jockusch, H. |
Abstract | Tumor necrosis factor α (TNF-α) is a potent cytokine in neurodegenerative disorders, but its precise role in particular brain disorders is ambiguous. In motor neuron (MN) disease of the mouse, exemplified by the model wobbler (WR), TNF-α causes upregulation of the metalloprotease-disintegrin ADAM8 (A8) in affected brain regions, spinal cord, and brainstem. The functional role of A8 during MN degeneration in the wobbler CNS was investigated by crossing WR with A8-deficient mice: a severely aggravated neuropathology was observed for A8-deficient WR compared with WR A8+/− mice, judged by drastically reduced survival [7 vs 81% survival at postnatal day 50 (P50)], accelerated force loss in the forelimbs, and terminal akinesis. In vitro protease assays using soluble A8 indicated specific cleavage of a TNF-α receptor 1 (p55 TNF-R1) but not a TNF-R2 peptide. Cleavage of TNF-R1 was confirmed in situ, because levels of soluble TNF-R1 were increased in spinal cords of standard WR compared with wild-type mice but not in A8-deficient WR mice. In isolated primary neurons and microglia, TNF-α-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-α showed higher toxicity for cultured neurons from A8-deficient than for those from wild-type mice, demonstrating that TNF-R1 shedding by A8 is neuroprotective. Our results indicate an essential role for ADAM8 in modulating TNF-α signaling in CNS diseases: a feedback loop integrating TNF-α, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-α mediated neuroprotection in situ and a rationale for therapeutic intervention. |
Research Group | Biophysics and Bioengineering group |
Publisher | Society for Neuroscience |
Journal | Journal of Neuroscience |
ISSN | 0270-6474 |
Publication dates | |
Sep 2010 | |
Publication process dates | |
Deposited | 11 Jul 2013 |
Output status | Published |
Digital Object Identifier (DOI) | https://doi.org/10.1523/JNEUROSCI.1520-10.2010 |
Language | English |
https://repository.mdx.ac.uk/item/8431z
54
total views0
total downloads4
views this month0
downloads this month