Hierarchical recruitment by AMPA but not staurosporine of pro‐apoptotic mitochondrial signaling in cultured cortical neurons: evidence for caspase‐dependent/independent cross‐talk

Beart, Philip M; Lim, Maria L. R.; Chen, Baohong; Diwakarla, Shanti; Mercer, Linda D; Cheung, Nam Sang; Nagley, Phillip

doi:10.1111/j.1471-4159.2007.04937.x

Cited by 20 publications

(66 citation statements)

References 51 publications

(165 reference statements)

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“…Staurosporine (STS), a classical apoptotic stimulus that has been previously widely characterized to induce apoptosis in several different cell types including primary neuronal cultures, [25][26][27] was used to promote apoptosis in primary cultures of cortical neurons. In the present experiments, 1 μM STS induced neuronal death as demonstrated by a progressive increase in the number of pyknotic nuclei from 6 h of STS treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our observations on caspase-3 and AIF release and protection by caspase-inhibition agree with previous studies on STS-treated on cortical neurons. 25,26 Only a few studies have reported STSinduced autophagy in unmodified cells 34,35 especially in cortical neurons, 36 but in specific conditions, such as in fibroblast mutants incompetent for apoptosis, STS has been reported to cause autophagic cell death that is blocked by 3-MA or by knockdown of Atg5 or Beclin 1.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Beclin 1-independent autophagy contributes to apoptosis in cortical neurons

Grishchuk¹,

Ginet²,

Truttmann³

et al. 2011

Autophagy

160

127

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Beclin 1-independent autophagy contributes to apoptosis in cortical neurons

Grishchuk¹,

Ginet²,

Truttmann³

et al. 2011

Autophagy

160

127

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“…Hence, whereas staurosporine treatment elicited an apoptotic injury, 25 glutamate exposure triggered a nonapoptotic, presumably necrotic injury in neuronal culture. 26 Despite eliciting different types of injury, both staurosporine and glutamate treatment caused an immediate increase in tPA-binding, in line with our initial observation that tPA binds to nonviable neurons in culture ( Figure 1C,E).…”

Section: Tpa Binds To Injured Neurons In Vitromentioning

confidence: 92%

A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury

Samson

Borg

Niego

et al. 2009

Blood

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Tissue-type plasminogen activator (tPA) is an extracellular protease that converts plasminogen into plasmin. For tPA to generate plasmin under biologic conditions, a cofactor must first bring tPA and plasminogen into physical proximity. Fibrin provides this cofactor for tPAmediated plasmin generation in blood. Despite being naturally devoid of fibrin(ogen), tPA-mediated plasmin formation also occurs in the brain. The fibrin-like cofactor(s) that facilitates plasmin formation in the injured brain has remained unknown. Here we show that protein aggregates formed during neuronal injury provide a macromolecular, nonfibrin cofactor that promotes tPA-mediated plasmin formation and subsequent cell breakdown. The binding of plasminogen and tPA to these protein aggregates occurs via distinct mechanisms. Importantly, nonneuronal cell types also exhibit this cofactor effect upon injury, indicating a general phenomenon. This novel cofactor identified in nonviable cells has ramifications for ischemic stroke where tPA is used clinically and where plasmin activity within the injured brain is unwanted. A means of selectively inhibiting the binding of tPA to nonviable cells while preserving its association with fibrin may be of benefit for the treatment of ischemic stroke. (Blood. 2009;114:1937-1946 IntroductionTissue-type plasminogen activator (tPA) is a multidomain 70-kDa extracellular glycoprotein that converts inactive plasminogen into the broad-acting protease plasmin. 1,2 For tPA to generate plasmin optimally in the blood, both tPA and plasminogen must first bind to fibrin. 2,3 The physical colocalization of tPA and plasminogen on the fibrin surface significantly facilitates tPA-mediated plasmin generation and subsequent fibrinolysis. 2,4 Hence, fibrin acts as both a cofactor for tPA-mediated plasmin formation and as a substrate for plasmin. 3 In contrast to the blood, the brain is devoid of fibrin. 5-7 Nevertheless, tPA-mediated plasmin generation is also important for brain function and dysfunction. 8,9 Indeed, tPA-mediated plasmin formation in the brain has been shown to be neurotoxic. [10][11][12][13] For instance, it was shown that hippocampal neurons of tPA Ϫ/Ϫ and plasminogen Ϫ/Ϫ mice were resistant to excitotoxic cell death, whereas administration of exogenous tPA restored sensitivity to excitotoxic injury in tPA Ϫ/Ϫ but not plasminogen Ϫ/Ϫ mice. [14][15][16] Furthermore, fibrinogen Ϫ/Ϫ mice were found to be as vulnerable to intrahippocampal excitotoxicity as wild-type mice, although genetic ablation of plasminogen on either background conferred equal protection from excitotoxic injury. 15 Hence, fibrinindependent tPA-mediated plasmin generation sensitizes neurons to excitotoxicity-an insult that contributes to infarction during stroke, 17 traumatic brain injury, 18 and numerous other neurodegenerative paradigms. Whereas ␤-amyloid and NG2 are likely cofactors for plasmin generation during Alzheimer disease 19 and spinal cord injury, 20 respectively, the "fibrin-like" cofactor that promotes tPA-mediated plasmin for...

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“…Knockdown of these proteins via short interfering RNA (siRNA) protects these cells from paraquat treatment. Translocation of Bax and Bak to the OMM initiates outer mitochondrial membrane permeabilization (OMMP), resulting in the redistribution of pro-apoptotic factors from the mitochondrial IMS, such as cyt c, Smac/DIABLO and HtrA2/Omi which are essential for the activation of downstream effector caspase-3 and caspase-7, ultimately leading to neuronal cell death [86][87][88].…”

Section: Chronic Oxidative Stress and Pcd: Apoptosis And Autophagymentioning

confidence: 99%

Oxidative Stress: Emerging Mitochondrial and Cellular Themes and Variations in Neuronal Injury

Higgins

Beart

Shin

et al. 2010

JAD

Self Cite

134

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Abstract. Oxidative stress plays a central role in neuronal injury and cell death in acute and chronic pathological conditions. The cellular responses to oxidative stress embrace changes in mitochondria and other organelles, notably endoplasmic reticulum, and can lead to a number of cell death paradigms, which cover a spectrum from apoptosis to necrosis and include autophagy. In Alzheimer's disease, and other pathologies including Parkinson's disease, protein aggregation provides further cellular stresses that can initiate or feed into the pathways to cell death engendered by oxidative stress. Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse modes of cell death mediated by mitochondria under oxidative stress. Novel insights into cellular responses to neuronal oxidative stress from a range of different stressors can be gained by detailed transcriptomics analyses. Such studies at the cellular level provide the key for understanding the molecular and cellular pathways whereby neurons respond to oxidative stress and undergo injury and death. These considerations underpin the development of detailed knowledge in more complex integrated systems, up to the intact human bearing the neuropathology, facilitating therapeutic advances.

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Hierarchical recruitment by AMPA but not staurosporine of pro‐apoptotic mitochondrial signaling in cultured cortical neurons: evidence for caspase‐dependent/independent cross‐talk

Cited by 20 publications

References 51 publications

Beclin 1-independent autophagy contributes to apoptosis in cortical neurons

Beclin 1-independent autophagy contributes to apoptosis in cortical neurons

A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury

Oxidative Stress: Emerging Mitochondrial and Cellular Themes and Variations in Neuronal Injury

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