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, Jing; 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; Larissa, Mosch; Bernard, René; Grittner, Ulrike; Balkaya, Mustafa; Kronenberg, Golo; Dirnagl, Ulrich; Endres, Matthias; Harms, Christoph

doi:10.1523/jneurosci.4428-15.2016

Cited by 21 publications

(20 citation statements)

References 58 publications

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“…Mice will be subjected to 45 minutes filamentous temporary middle cerebral artery occlusion (tMCAo), and will be killed for histological and biochemical analyses after 3, 5, or 21 days, respectively. The filamentous tMCAo model will be performed using Dirnagl et al ’s method (doi: 10.1038/npre.2010.3492.2 ) as implemented in our laboratory 19 – 21 . For pain relief, Bupivacaine gel is topically applied in the wound, and the wound is temporally closed with an adaptive suture.…”

Section: Methodsmentioning

confidence: 99%

“…DeSimoni’s neuroscore 27 , a composite of general behavioral alterations and focal motor, sensory, reflex, and balance deficits, will be performed at days 1, 2, 7, 14 and 21 following cerebral ischemia as implemented in our laboratory 19 . In brief, general health and behavioral alterations and specific focal deficits will be scored separately and subsequently added to form a summation score.…”

Section: Methodsmentioning

confidence: 99%

“…The Rotarod, a widely used test of motor coordination and learning, will be performed at days 2, 7, and 14 following cerebral ischemia as implemented in our laboratory 19 . The best run of three runs per time point will be used for statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

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Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo)

et al. 2018

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Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our understanding of the cross talk between the ischemic brain and the immune system is limited. Recently, we demonstrated that following focal ischemia, death of mature viable neurons can be executed through phagocytosis by microglial cells or recruited macrophages, i.e. through phagoptosis. It was shown that inhibition of phagocytic signaling pathways following endothelin-1 induced focal cerebral ischemia leads to increased neuronal survival and neurological recovery. This suggests that inhibition of specific phagocytic pathways may prevent neuronal death during cerebral ischemia. To further explore this potential therapeutic target, we propose to assess the role of phagocytosis in an established model of temporary (45min) middle cerebral artery occlusion (tMCAo), and to evaluate neuronal survival and neurological recovery in mice with deficient phagocytosis. The primary outcome of this study will be forelimb function assessed with the staircase test. Secondary outcomes constitute Rotarod performance, stroke volume (quantified on MR imaging or brain sections, respectively), diffusion tensor imaging (DTI) connectome mapping, and histological analyses to measure neuronal and microglial densities, and phagocytic activity. Male mice aged 10-12 weeks will be used for experiments.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo)

et al. 2018

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show abstract

“…The filamentous tMCAo model will be performed using Dirnagl et al ’s method (doi: 10.1038/npre.2010.3492.2) as implemented in our laboratory 19– 21 . For pain relief, Bupivacaine gel is topically applied in the wound, and the wound is temporally closed with an adaptive suture.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo)

et al. 2017

View full text Add to dashboard Cite

Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our understanding of the cross talk between the ischemic brain and the immune system is limited. Recently, we demonstrated that following focal ischemia, death of mature viable neurons can be executed through phagocytosis by microglial cells or recruited macrophages, i.e. through phagoptosis. It was shown that inhibition of phagocytic signaling pathways following endothelin-1 induced focal cerebral ischemia leads to increased neuronal survival and neurological recovery. This suggests that inhibition of specific phagocytic pathways may prevent neuronal death during cerebral ischemia. To further explore this potential therapeutic target, we propose to assess the role of phagocytosis in an established model of temporary (45min) middle cerebral artery occlusion, and to evaluate neuronal survival and neurological recovery in mice with deficient phagocytosis.

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Molecular basis for the effect of the L31F mutation on CARD function in ARC

Park

2017

FEBS Letters

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The apoptosis repressor with caspase-recruiting domain (ARC) is aberrantly overexpressed in various cancers. ARC contains a caspase recruitment domain (CARD) that is the main mediator of protein-protein interactions. Mutation of Leu31 within the CARD of ARC to Phe (ARC_L31F) is widely used as a functionally defective mutant of ARC despite a lack of clear experimental evidence regarding how its functionality is lost. In this study, we show that L31 in helix 2 (H2) is critical for stabilization of the helix bundle fold in the CARD domain. In addition, the L31F mutation disrupts homodimer formation that is critical to ARC functions. Our current study reveals the molecular basis for the L31F mutation disrupting the ARC CARD functions.

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Interaction of ARC and Daxx: A Novel Endogenous Target to Preserve Motor Function and Cell Loss after Focal Brain Ischemia in Mice

Cited by 21 publications

References 58 publications

Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo)

Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo)

Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo)

Molecular basis for the effect of the L31F mutation on CARD function in ARC

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