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Interaction of ARC and Daxx: a novel endogenous target to\ud preserve motor function and cell loss after focal brain\ud ischemia in mice
- Source :
- The journal of neuroscience 36(31), 8132-8148 (2016). doi:10.1523/JNEUROSCI.4428-15.2016, The Journal of Neuroscience, 36 (31)
- Publication Year :
- 2016
- Publisher :
- Society for Neuroscience, 2016.
-
Abstract
- 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 endogenous ARC protein 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 (1 μg 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.<br />The Journal of Neuroscience, 36 (31)<br />ISSN:0270-6474<br />ISSN:1529-2401
- Subjects :
- Male
0301 basic medicine
Pathology
Apoptosis
Pharmacology
metabolism [Cytoskeletal Proteins]
Brain ischemia
Endogenous neuroprotection
Mice
0302 clinical medicine
Protein Interaction Maps
metabolism [Gene Products, tat]
Arc (protein)
General Neuroscience
Penumbra
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Articles
Behavioral outcome
Middle cerebral artery occlusion
TAT protein transduction
Gene Products, tat
Middle cerebral artery
Function and Dysfunction of the Nervous System
Co-Repressor Proteins
metabolism [Intracellular Signaling Peptides and Proteins]
metabolism [Nuclear Proteins]
Protein Binding
medicine.medical_specialty
Daxx protein, mouse
metabolism [Brain Ischemia]
Ischemia
Nerve Tissue Proteins
pathology [Brain Ischemia]
Neuroprotection
03 medical and health sciences
Death-associated protein 6
medicine.artery
medicine
Animals
ddc:610
activity regulated cytoskeletal-associated protein
metabolism [Nerve Tissue Proteins]
business.industry
Ischemic cascade
medicine.disease
Mice, Inbred C57BL
Cytoskeletal Proteins
030104 developmental biology
Carrier Proteins
business
030217 neurology & neurosurgery
metabolism [Carrier Proteins]
Molecular Chaperones
Subjects
Details
- Language :
- English
- ISSN :
- 02706474 and 15292401
- Database :
- OpenAIRE
- Journal :
- The journal of neuroscience 36(31), 8132-8148 (2016). doi:10.1523/JNEUROSCI.4428-15.2016, The Journal of Neuroscience, 36 (31)
- Accession number :
- edsair.doi.dedup.....380e4f17eb4f98bac95a08f9339b5360