Control of death receptor and mitochondrial‐dependent apoptosis by c‐Jun N‐terminal kinase in hippocampal CA1 neurones following global transient ischaemia

Carboni, Susanna; Antonsson, Bruno; Gaillard, P.; Gotteland, Jean‐Pierre; Gillon, Jean‐Yves; Vitte, Pierre-Alain

doi:10.1111/j.1471-4159.2004.02925.x

Cited by 58 publications

(42 citation statements)

References 30 publications

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“…This may be because of early cell death by necrosis during the initial HII; delayed cell death by apoptosis (a relatively late event in this model) might therefore be specifically associated with JNK3 activation. In support of this notion, continuous JNK activation is required for several hours for neuronal apoptosis induced by HII and even the relatively late inhibition of JNK after injury is still protective (Borsello et al, 2003;Carboni et al, 2005). After cerebral HII, the combined activation of excitatory amino-acid receptors and the increased formation of oxygen free radicals and of intracellular Ca 2 + (Takita et al, 2004) are possible triggers for JNK3 activation.…”

Section: Discussionmentioning

confidence: 92%

Deletion of the c-Jun N-terminal Kinase 3 Gene Protects Neonatal Mice against Cerebral Hypoxic—Ischaemic Injury

Pirianov

Brywe²,

Mallard³

et al. 2006

J Cereb Blood Flow Metab

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c-Jun N-terminal kinase 3 (JNK3) is a member of the stress-activated group of mitogen-activated protein kinases. c-Jun N-terminal kinase 3 is a potent mediator of apoptosis and the use of JNK inhibitors or jnk3 gene deletion each protect against brain injury in adults. However, little is known about the role of JNK3 or its mechanism of action in neonatal brain injury. The aim of the present study was to compare the vulnerability of neonatal JNK3 knockout (JNK3 KO) mice and wild-type (WT) mice to cerebral hypoxic-ischaemic injury (HII) using unilateral-carotid occlusion combined with transient hypoxia. The degree of neural tissue loss in JNK3 KO mice was substantially reduced compared with WT mice (JNK3 KO 27.8%62.8% versus WT 48.3%62.0%, P < -0.0001) after HII. Significant attenuation of injury was observed in the cerebral cortex, hippocampus, striatum, and thalamus of JNK3 KO compared with WT mice. Hypoxic-ischaemic injury increased JNK phosphorylation and activity, with JNK3 as the major isoform. Significantly, in JNK3 KO animals there was no difference in the activation of the upstream kinases mitogen-activated protein kinase kinase (MKK4) or MKK7. Downstream of JNK3, HII lead to increased phosphorylation of the transcription factors c-Jun and adenovirus transcription factor-2 (ATF-2), which was attenuated in JNK3 KO mice. c-Jun N-terminal kinase 3 deletion also decrease caspase-3 cleavage and Bim/PUMA expression, coupled with a upregulation of AKT/FOXO3a levels, linking JNK3 to apoptosis. These findings implicate JNK3 involvement in neural cell loss resulting from cerebral HII in the developing brain.

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Section: Discussionmentioning

confidence: 92%

Deletion of the c-Jun N-terminal Kinase 3 Gene Protects Neonatal Mice against Cerebral Hypoxic—Ischaemic Injury

Pirianov

Brywe²,

Mallard³

et al. 2006

J Cereb Blood Flow Metab

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show abstract

“…In addition, increased cytochrome c release has been detected in ischemic tissues in animal models (38). In a previous study, we showed that global transient ischemia in the gerbil model induces two waves of apoptosis; however, only the second one is associated with significant cytochrome c release (41). The first wave is associated with caspase-8 activation, whereas activation of caspase-3 is detected in both waves.…”

Section: Discussionmentioning

confidence: 99%

Bax Channel Inhibitors Prevent Mitochondrion-mediated Apoptosis and Protect Neurons in a Model of Global Brain Ischemia

Hetz

Vitte²,

Bombrun³

et al. 2005

Journal of Biological Chemistry

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150

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Ischemic injuries are associated with several pathological conditions, including stroke and myocardial infarction. Several studies have indicated extensive apoptotic cell death in the infarcted area as well as in the penumbra region of the infarcted tissue. Studies with transgenic animals suggest that the mitochondrion-mediated apoptosis pathway is involved in ischemia-related cell death. This pathway is triggered by activation of pro-apoptotic Bcl-2 family members such as Bax. Here, we have identified and synthesized two low molecular weight compounds that block Bax channel activity. The Bax channel inhibitors prevented cytochrome c release from mitochondria, inhibited the decrease in the mitochondrial membrane potential, and protected cells against apoptosis. The Bax channel inhibitors did not affect the conformational activation of Bax or its translocation and insertion into the mitochondrial membrane in cells undergoing apoptosis. Furthermore, the compounds protected neurons in an animal model of global brain ischemia. The protective effect in the animal model correlated with decreased cytochrome c release in the infarcted area. This is the first demonstration that Bax channel activity is required in apoptosis.Apoptosis is a conserved cell death mechanism essential for normal development and tissue homeostasis in multicellular organisms. Although apoptosis presumably participates in the development of all cell lineages, aberrations in the expression of pro-or anti-apoptotic proteins have been implicated in the initiation of a variety of human diseases, including arteriosclerosis, heart failure, infertility, autoimmunity, immunodeficiency, and cancer, in addition to diseases affecting the nervous system such as neurodegeneration and ischemia (1-3). Several intracellular apoptosis signaling pathways have been identified, including the death receptor pathway and the mitochondrial pathway (4 -6). The induction of apoptosis ultimately converges upon the activation of cysteine proteases of the caspase family. The Bcl-2 family proteins are located upstream at organelle membranes and control the activation of downstream caspases, representing a critical proximal intracellular checkpoint in the mitochondrial apoptosis pathway. The Bcl-2 family is composed of pro-and anti-apoptotic members. Anti-apoptotic Bcl-2 family members display sequence homology in four ␣-helical domains called BH1-BH4.3 Pro-apoptotic Bcl-2 members can be further subdivided into more fully conserved, "multidomain" members with homology in the BH1-BH3 domains (e.g. Bax and Bak) or the "BH3-only" members (e.g. Bid, Bad, and Bim). Genetic and biochemical analyses indicate that the multidomain proteins Bax and Bak function as the essential gateway to the intrinsic cell death pathway operating at the mitochondria. The upstream BH3-only members respond to particular apoptotic signals and subsequently, either directly or indirectly, trigger the conformational activation of Bax and/or Bak. Overexpression of the anti-apoptotic protein Bcl-2 or deletion o...

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“…[29][30][31][32] Therefore, it was hypothesized that (G2019S) LRRK2 causes degeneration of SNpc dopaminergic neurons in (G2019S) LRRK2 mice by promoting the formation of active caspase-9, caspase-8, and caspase-3. In accordance with this hypothesis, protein level of cleaved active caspase-9, active caspase-8, or active caspase-3 was greatly increased in the SN of 12-month-old (G2019S) LRRK2 mice (Figure 7a).…”

Section: Resultsmentioning

confidence: 99%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

155

151

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(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve-to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser 257 , and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63 , downstream targets of phospho-MKK4 Ser257 , was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63 , and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

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Control of death receptor and mitochondrial‐dependent apoptosis by c‐Jun N‐terminal kinase in hippocampal CA1 neurones following global transient ischaemia

Cited by 58 publications

References 30 publications

Deletion of the c-Jun N-terminal Kinase 3 Gene Protects Neonatal Mice against Cerebral Hypoxic—Ischaemic Injury

Deletion of the c-Jun N-terminal Kinase 3 Gene Protects Neonatal Mice against Cerebral Hypoxic—Ischaemic Injury

Bax Channel Inhibitors Prevent Mitochondrion-mediated Apoptosis and Protect Neurons in a Model of Global Brain Ischemia

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

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