Fas Receptor and Neuronal Cell Death after Spinal Cord Ischemia

Matsushita, Kohji; Wu, Yongqin; Qiu, Jianhua; Lang-Lazdunski, Loı̈c; Hirt, Lorenz; Waeber, Christian; Hyman, Bradley T.; Yuan, Junying; Moskowitz, Michael A.

doi:10.1523/jneurosci.20-18-06879.2000

Cited by 127 publications

(81 citation statements)

References 52 publications

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“…In spinal cord ischemia, Matsushita and colleagues found that (i) Fas expression was increased within hours, (ii) caspase-8 was cleaved within 1.5 h and (iii) the Fas DISC complex was detectable in these early time periods [29]. These findings are strikingly similar to ours and indicate that Fas-related mechanisms of cell death may be common between these two models.…”

Section: Fas and Brain Injurysupporting

confidence: 85%

Caspase activation in fetal rat brain following experimental intrauterine inflammation

Sharangpani¹,

Takanohashi²,

Bell³

2008

Brain Research

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Intrauterine inflammation has been implicated in developmental brain injuries, including the development of periventricular leukomalacia (PVL) and cerebral palsy (CP). Previous studies in our rat model of intrauterine inflammation demonstrated apoptotic cell death in fetal brains within the first 5 days after lipopolysaccharide (LPS) administration to mothers and eventual dysmyelination. Cysteine-containing, aspartate-specific proteases, or caspases, are proteins involved with apoptosis through both intracellular (intrinsic pathway) and extracellular (extrinsic pathway) mechanisms. We hypothesized that cell death in our model would occur mainly via activation of the extrinsic pathway. We further hypothesized that Fas, a member of the tumor necrosis factor receptor (TNFR) superfamily, would be increased and the death inducing signaling complex (DISC) would be detectable. Pregnant rats were injected intracervically with LPS at E15 and immunoblotting, immunohistochemical and immunoprecipitation analyses were performed. The presence of the activated form of the effector caspase (caspase-3) was observed 24 h after LPS administration. Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h, (ii) caspase-8 at 2 h and (iii) caspase-3 at 4 h. At 24 h after LPS, activated caspase-3 + /Fas + cells were observed within the developing white matter. Lastly, the DISC complex (caspase-8, Fas and Fasassociated Death Domain (FADD)) was observed within 30 min by immunoprecipitation. Apoptosis in our model occurs via both extrinsic and intrinsic pathways, and activation of Fas may play a role. Understanding the mechanisms of cell death in models of intrauterine inflammation may affect development of future strategies to mitigate these injuries in children.

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Section: Fas and Brain Injurysupporting

confidence: 85%

Caspase activation in fetal rat brain following experimental intrauterine inflammation

Sharangpani¹,

Takanohashi²,

Bell³

2008

Brain Research

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“…Involvement of other members of the death receptor family, Fas and FasL, in active neuron killing during I/R has attracted significant attention (39,40). Both molecules were activated during brain I/R.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

Ishibashi

Prokopenko

Reuhl

et al. 2002

The Journal of Immunology

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Stroke is one of the leading causes of death in major industrial countries. Many factors contribute to the cellular damage resulting from ischemia/reperfusion (I/R). Experimental data indicate an important role for oxidative stress and the inflammatory cascade during I/R. We are testing the hypothesis that the mechanism of protection against I/R damage observed in transgenic mice overexpressing human antioxidant enzymes (particularly intracellular glutathione peroxidase) involves the modulation of inflammatory response as well as reduced sensitivity of neurons to cytotoxic cytokines. Transgenic animals show significant reduction of expression of chemokines, IL-6, and cell death-inducing ligands as well as corresponding receptors in a focal cerebral I/R model. Reduction of DNA binding activity of consensus and potential AP-1 binding sites in mouse Fas ligand promoter sequence was observed in nuclear extracts from transgenic mice overexpressing intracellular glutathione peroxidase compared with normal animals following I/R. This effect was accompanied by modulation of the c-Jun N-terminal kinase/stress-activated protein kinase pathway. Cultured primary neurons from the transgenic mice demonstrated protection against hypoxia/reoxygenation injury as well as cytotoxicity after TNF-α and Fas ligand treatment. These results indicate that glutathione peroxidase-sensitive reactive oxygen species play an important role in regulation of cell death during cerebral I/R by modulating intrinsic neuronal sensitivity as well as brain inflammatory reactions.

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“…We found that not only the Fas receptor, as shown in ref. 21, but also its endogenous ligand FasL and its signaling intermediate Daxx were expressed in control spinal cord (Fig. 4A).…”

Section: Functional Evidence For a Role Of The No͞fas Feedback Loop Imentioning

confidence: 96%

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Raoul

Buhler

Sadeghi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1 G93A and SOD1 G85R , but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas͞NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1 G93A and SOD1 G85R mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas͞NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.cell death ͉ motoneuron disease ͉ NO ͉ p38 kinase ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is the most frequent adultonset motoneuron disease in humans. ALS is characterized by the selective degeneration of motoneurons in spinal cord, brainstem, and cerebral cortex leading to muscle atrophy and paralysis and ultimately to death. About 1 to 2% of all human ALS forms are caused by dominantly inherited mutations in the Cu͞Zn superoxide dismutase (SOD1) gene. Mice transgenic for the ALS-linked SOD1 mutations G37R (1), H46R͞H48Q (2), G85R (3), and G93A (4) develop an adult-onset motoneuron disorder that remarkably resembles human ALS.Despite much intensive study, many questions remain concerning the mechanism(s) by which mutant SOD1 triggers specific motoneuron death. One unresolved issue is the cellular site of action of the gain-of-function mutations. Clement et al. (5) generated chimeric mice carrying a mixture of WT and mutant SOD1-expressing cells in the spinal cord. In these mice, WT motoneurons eventually showed stigmata of degeneration, whereas some mutant SOD1 motoneurons were protected from degeneration when surrounded by WT nonneuronal cells. These results suggest that mutant SOD1 in both motoneurons and surrounding cells may play a role in the disease process.Our earlier studies using cultures of purified embryonic motoneurons reached similar conclusions. We found that motoneurons from SOD1 G93A , SOD1 G37R , and SOD1 G85R mice survived normally in the presence of optimal trophic support or when challenged by excitotoxic agonists. In marked contrast, compared with controls, they displayed a 10-to 100-fold increase in sensitivity to extracellular agonists of the Fas receptor or to exogenous nitr...

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Fas Receptor and Neuronal Cell Death after Spinal Cord Ischemia

Cited by 127 publications

References 52 publications

Caspase activation in fetal rat brain following experimental intrauterine inflammation

Caspase activation in fetal rat brain following experimental intrauterine inflammation

Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

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