Cleavage of Bid May Amplify Caspase-8-Induced Neuronal Death Following Focally Evoked Limbic Seizures

Henshall, David C.; Bonislawski, David P.; Skradski, Shana L.; Lan, Jing-Quan; Meller, Robert; Simon, Roger P.

doi:10.1006/nbdi.2001.0415

Cited by 106 publications

(132 citation statements)

References 46 publications

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“…It is well established that the extrinsic signalling pathway that initiates apoptosis involves death receptor members of the Tnf receptor gene superfamily [21,23,26,42,46,47]. Our study demonstrated that Fas, Tnfr1, Fasl and Tnf genes were highly expressed in the hippocampus following KA treatment in wild-type animals.…”

Section: Discussionsupporting

confidence: 50%

“…The Fas receptor is known to induce apoptosis by binding to FasL. Thus, the Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are upregulated following experimental KA administration to rodents [21][22][23]. In addition, previous studies have shown that the binding of the Fas ligand to FasR triggers the formation of a death-inducing signalling complex (DISC), which consists of FasL, FasR, the adapter protein FADD (Fas-associated death domain protein), and the TNFR1-associated death domain protein (TRADD) to induce the activation of caspase-8, a protease which then activates downstream effector caspase-3, which in turn is responsible for apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

et al. 2014

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The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT 2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the upregulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.

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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

et al. 2014

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“…For instance, calpain, a ubiquitous calcium-sensitive protease which has a dozen identified substrates, has been shown to be activated in neurons during several pathologies including epilepsy (Bi et al 1996;Rami et al 1997;Vanderklish and Bahr 2000). In addition, caspase proteases are reported to be involved in number of seizure models leading to neuronal death (Henshall et al 2000(Henshall et al , 2001a. Thus, it is possible that PIMT could be targeted by proteases activated in neurons of the hippocampus during seizures.…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Lanthier

Bouthillier

Lapointe

et al. 2002

Journal of Neurochemistry

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Protein L-isoaspartyl methyltransferase (PIMT) repairs the damaged proteins which have accumulated abnormal aspartyl residues during cell aging. Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures. Here we investigated the role of PIMT in human mesial temporal lobe epilepsy. Using surgical specimens of hippocampus and neocortex from controls and epileptic patients, we showed that PIMT activity and expression were 50% lower in epileptic hippocampus than in controls but were unchanged in neocortex. Although the protein was down-regulated, PIMT mRNA expression was unchanged in epileptic hippocampus, suggesting post-translational regulation of the PIMT level. Moreover, several proteins with abnormal aspartyl residues accumulate in epileptic hippocampus. Microtubules component b-tubulin, one of the major PIMT substrates, had an increased amount (two-fold) of L-isoaspartyl residues in the epileptic hippocampus. These results demonstrate that the down-regulation of PIMT in epileptic hippocampus leads to a significant accumulation of damaged tubulin that could contribute to neuron dysfunction in human mesial temporal lobe epilepsy.

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“…This early period following seizures coincides with significant upregulation of Bcl2, activation of Fas and FADD death receptor signaling, and caspasemediated activation of a large number of proteins regulating pro-and antiapoptotic control points in the seizureinduced cell death pathway. 41,42 Mcl1 is upregulated by cytokines such as interleukin-6 (IL6) acting through the JAK/ STAT pathway and interferon alpha, [43][44][45][46] by activin via the TGFb pathway 47 and by MEK, implicating the Ras/MEK/ MAPK pathway in Mcl1 transcription. 48 Since activity within these linked pathways increases rapidly in CNS ischemia and epilepsy, [49][50][51] the elevated transcription of Mcl1 may depend on the participation of a wide range of early inflammatory response signaling in the brain.…”

Section: Functional Link Of Mcl1 To Neuroprotection In Epileptic Brainmentioning

confidence: 99%

Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons

et al. 2004

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Mcl1 is a Bcl2-related antiapoptotic protein originally isolated from human myeloid leukemia cells. Unlike Bcl2, expression has not been reported in CNS neurons. We isolated Mcl1 in a direct screen for candidate modifier genes of neuronal vulnerability by differential display of mRNAs upregulated following prolonged seizures in two mouse strains with contrasting levels of hippocampal cell death. Mcl1 is widely expressed in neurons, and transcription is rapidly induced in both strains. In resistant C57Bl/6J mice, Mcl1 protein levels remain persistently elevated in hippocampal pyramidal neurons after seizures, but fall rapidly in C3H/HeJ hippocampus, coinciding with extensive neuronal apoptosis. DNA damage and caspase-mediated cell death were strikingly increased in Mcl1-deficient mice when compared to þ / þ littermates after similar seizures. We identify Mcl1 as a neuronal gene responsive to excitotoxic insult in the brain, and link relative levels of Mcl1 expression to inherited differences in neuronal thresholds for apoptosis.

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Cleavage of Bid May Amplify Caspase-8-Induced Neuronal Death Following Focally Evoked Limbic Seizures

Cited by 106 publications

References 46 publications

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons

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