In vitro induction of neuronal apoptosis by anti-Fas antibody-containing sera from amyotrophic lateral sclerosis patients

Yi, F.H.; Lautrette, Christophe; Vermot-Desroches, Claudine; Bron, Dominique; Couratier, Philippe; Wijdenes, John; Preud'homme, J L; Jauberteau, Marie‐Odile

doi:10.1016/s0165-5728(00)00288-5

Cited by 72 publications

(55 citation statements)

References 57 publications

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“…In the context of ALS, the Fas͞NO feedback loop is of particular interest because it involves an extracellular step and diffusible factors. The cell death trigger NO is known to be produced not only by motoneurons but also by microglia and activated astrocytes (34,39) and Fas agonists have been detected in sera of patients with sporadic ALS (40). ''Community effects'' may thus allow for cellular neighbors to accelerate or to inhibit motoneuron death (5) and also underlie the clinical finding that ALS often progresses locally, between adjacent muscles or motor pools.…”

Section: Discussionmentioning

confidence: 99%

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.

100

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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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Section: Discussionmentioning

confidence: 99%

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.

100

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“…Numerous IgG antibodies and complement proteins are found in sera (117) from ALS patients, and antibody titer was positively associated with increased disease severity (118). Monoclonal Igs were detectable in 60% of sporadic ALS patients (119), and autoantibodies against ganglioside GM1 and GD1a (120), sulfoglucuronylparagloboside (121), neurofilament proteins (121), the TNF receptor family member FAS (CD95) (122), and voltage-gated Ca 2+ channels (123,124) have all been reported, indicating that ALS patients generate antibody responses to a variety of autoantigens.…”

Section: Inflammation and Autoimmunity In Als/ftdmentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

142

102

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Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

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“…At least 5 fields (observed at X 200) were counted in each assay to determine mean and standard errors. We also measured apoptosis using a photometric enzyme-immunoassay for the in-vitro determination of cytoplasmic histone-associated-DNA-fragments (mono-and oligonucleosomes) generated by DNA degradation (Cell Death Detection ELISA PLUS , Roche, Mannheim, Germany) according to the manufacturer's instructions, as previously described [35]. Experiments were performed in duplicate and repeated thrice.…”

Section: Apoptosis Measurementmentioning

confidence: 99%

Increase of Fas-induced apoptosis by inhibition of extracellular phosphorylation of Fas receptor in Jurkat cell line

Lautrette¹,

Loum-Ribot²,

Petit³

et al. 2006

Apoptosis

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Apoptosis signalling through the Fas pathway requires several steps of aggregation of the Fas receptor in the membrane, including aggregation that may occur in the absence of Fas ligand. Association of Fas domains is determinant to signal transmission following Fas ligand binding to a specific domain. The domains involved in Fas aggregation are located in its extracellular region and contain three potential protein kinase C-binding motifs. We therefore studied the possibility that phosphorylation of the extracellular region of Fas might be implicated in the regulation of Fas-mediated apoptosis. Inhibition experiments of extracellular phosphorylation were performed in human Jurkat T leukemia cells with K252b, an impermeant protein-kinase inhibitor. Extracellular phosphorylation of Fas receptor was related to ecto-kinase, as assessed by the [gamma-(32)P] ATP labelling of Fas-116 kDa aggregates, suppressed by K252b inhibitor which significantly increased the sensitivity to Fas-mediated apoptosis. Ecto-PKC involvement was demonstrated by bisindolylmaleimide VIII, a selective inhibitor of protein kinase C which significantly increased both Fas aggregation in the membrane and Fas-mediated apoptosis and by the addition of the PKC pseudo-substrate 19-36 which inhibited the phosphorylation of 116 kDa Fas aggregates. These data support a role for Fas phosphorylation in the decreased sensitivity to apoptosis in the Jurkat T leukemia cell line.

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In vitro induction of neuronal apoptosis by anti-Fas antibody-containing sera from amyotrophic lateral sclerosis patients

Cited by 72 publications

References 57 publications

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

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

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Increase of Fas-induced apoptosis by inhibition of extracellular phosphorylation of Fas receptor in Jurkat cell line

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