Interaction of ARC and Daxx: a novel endogenous target to preserve motor function and cell loss after focal brain ischemia in mice
The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endog...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Society for Neuroscience
2016
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| Online Access: | https://eprints.nottingham.ac.uk/35711/ |
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| author | Donath, Stefan An, Junfeng Lee, Sabrina Lin Lin Gertz, Karen Datwyler, Anna Lena Harms, Ulrike Müller, Susanne Farr, Tracy D. Füchtemeier, Martina Lättig-Tünnemann, Gisela Lips, Janet Foddis, Marco Mosch, Larissa Bernard, Rene Grittner, Ulrike Balkaya, Mustafa Kronenberg, Golo Dirnagl, Ulrich Endres, Matthias Harms, Christoph |
| author_facet | Donath, Stefan An, Junfeng Lee, Sabrina Lin Lin Gertz, Karen Datwyler, Anna Lena Harms, Ulrike Müller, Susanne Farr, Tracy D. Füchtemeier, Martina Lättig-Tünnemann, Gisela Lips, Janet Foddis, Marco Mosch, Larissa Bernard, Rene Grittner, Ulrike Balkaya, Mustafa Kronenberg, Golo Dirnagl, Ulrich Endres, Matthias Harms, Christoph |
| author_sort | Donath, Stefan |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenousARCprotein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD).TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30±8% (mean±SD; p=0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1ug intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.β-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20±7% (mean±SD; p˃0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX–ASK1–JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1–JNK activation. Our work identifies for the first time ARC–DAXX binding to block ASK1–JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy. |
| first_indexed | 2025-11-14T19:27:24Z |
| format | Article |
| id | nottingham-35711 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T19:27:24Z |
| publishDate | 2016 |
| publisher | Society for Neuroscience |
| recordtype | eprints |
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| spelling | nottingham-357112017-10-14T06:41:42Z https://eprints.nottingham.ac.uk/35711/ Interaction of ARC and Daxx: a novel endogenous target to preserve motor function and cell loss after focal brain ischemia in mice Donath, Stefan An, Junfeng Lee, Sabrina Lin Lin Gertz, Karen Datwyler, Anna Lena Harms, Ulrike Müller, Susanne Farr, Tracy D. Füchtemeier, Martina Lättig-Tünnemann, Gisela Lips, Janet Foddis, Marco Mosch, Larissa Bernard, Rene Grittner, Ulrike Balkaya, Mustafa Kronenberg, Golo Dirnagl, Ulrich Endres, Matthias Harms, Christoph The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenousARCprotein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD).TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30±8% (mean±SD; p=0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1ug intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.β-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20±7% (mean±SD; p˃0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX–ASK1–JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1–JNK activation. Our work identifies for the first time ARC–DAXX binding to block ASK1–JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy. Society for Neuroscience 2016-08-03 Article PeerReviewed application/pdf en cc_by https://eprints.nottingham.ac.uk/35711/1/Donath2016JNeurosci36%208132-48%20full.pdf Donath, Stefan, An, Junfeng, Lee, Sabrina Lin Lin, Gertz, Karen, Datwyler, Anna Lena, Harms, Ulrike, Müller, Susanne, Farr, Tracy D., Füchtemeier, Martina, Lättig-Tünnemann, Gisela, Lips, Janet, Foddis, Marco, Mosch, Larissa, Bernard, Rene, Grittner, Ulrike, Balkaya, Mustafa, Kronenberg, Golo, Dirnagl, Ulrich, Endres, Matthias and Harms, Christoph (2016) Interaction of ARC and Daxx: a novel endogenous target to preserve motor function and cell loss after focal brain ischemia in mice. Journal of Neuroscience, 36 (31). pp. 8132-8148. ISSN 1529-2401 behavioral outcome brain ischemia endogenous neuroprotection middle cerebral artery occlusion penumbra TAT protein transduction http://www.jneurosci.org/content/36/31/8132 doi:10.1523/JNEUROSCI.4428-15.2016 doi:10.1523/JNEUROSCI.4428-15.2016 |
| spellingShingle | behavioral outcome brain ischemia endogenous neuroprotection middle cerebral artery occlusion penumbra TAT protein transduction Donath, Stefan An, Junfeng Lee, Sabrina Lin Lin Gertz, Karen Datwyler, Anna Lena Harms, Ulrike Müller, Susanne Farr, Tracy D. Füchtemeier, Martina Lättig-Tünnemann, Gisela Lips, Janet Foddis, Marco Mosch, Larissa Bernard, Rene Grittner, Ulrike Balkaya, Mustafa Kronenberg, Golo Dirnagl, Ulrich Endres, Matthias Harms, Christoph Interaction of ARC and Daxx: a novel endogenous target to preserve motor function and cell loss after focal brain ischemia in mice |
| title | Interaction of ARC and Daxx: a novel endogenous target to
preserve motor function and cell loss after focal brain
ischemia in mice |
| title_full | Interaction of ARC and Daxx: a novel endogenous target to
preserve motor function and cell loss after focal brain
ischemia in mice |
| title_fullStr | Interaction of ARC and Daxx: a novel endogenous target to
preserve motor function and cell loss after focal brain
ischemia in mice |
| title_full_unstemmed | Interaction of ARC and Daxx: a novel endogenous target to
preserve motor function and cell loss after focal brain
ischemia in mice |
| title_short | Interaction of ARC and Daxx: a novel endogenous target to
preserve motor function and cell loss after focal brain
ischemia in mice |
| title_sort | interaction of arc and daxx: a novel endogenous target to
preserve motor function and cell loss after focal brain
ischemia in mice |
| topic | behavioral outcome brain ischemia endogenous neuroprotection middle cerebral artery occlusion penumbra TAT protein transduction |
| url | https://eprints.nottingham.ac.uk/35711/ https://eprints.nottingham.ac.uk/35711/ https://eprints.nottingham.ac.uk/35711/ |