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Gavin C. Higgins Philip M. Beart Phillip Nagley 《Cellular and molecular life sciences : CMLS》2009,66(16):2773-2787
To characterize neuronal death, primary cortical neurons (C57/Black 6 J mice) were exposed to hydrogen peroxide (H2O2) and staurosporine. Both caused cell shrinkage, nuclear condensation, DNA fragmentation and loss of plasma membrane integrity.
Neither treatment induced caspase-7 activity, but caspase-3 was activated by staurosporine but not H2O2. Each treatment caused redistribution from mitochondria of both endonuclease G (Endo G) and cytochrome c. Neurons knocked down for Endo G expression using siRNA showed reduction in both nuclear condensation and DNA fragmentation
after treatment with H2O2, but not staurosporine. Endo G suppression protected cells against H2O2-induced cell death, while staurosporine-induced death was merely delayed. We conclude that staurosporine induces apoptosis
in these neurons, but severe oxidative stress leads to Endo G-dependent death, in the absence of caspase activation (programmed
cell death-type III). Therefore, oxidative stress triggers in neurons a form of necrosis that is a systematic cellular response
subject to molecular regulation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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Summary Muscimol, a potent GABA receptor agonist, produced increases in DOPAC and dopamine concentrations in the rat hypothalamus. GABAergic receptors, therefore, modulate hypothalamic dopaminergic neurones.This work was supported by the National health and Medical Research Council of Australia. The authors are grateful to Dr P. Krogsgaard-Larsen, Copenhagen, for providing muscimol. 相似文献
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Higgins GC Devenish RJ Beart PM Nagley P 《Cellular and molecular life sciences : CMLS》2011,68(22):3725-3740
Primary neurons undergo insult-dependent programmed cell death. We examined autophagy as a process contributing to cell death
in cortical neurons after treatment with either hydrogen peroxide (H2O2) or staurosporine. Although caspase-9 activation and cleavage of procaspase-3 were significant following staurosporine treatment,
neither was observed following H2O2 treatment, indicating a non-apoptotic death. Autophagic activity increased rapidly with H2O2, but slowly with staurosporine, as quantified by processing of endogenous LC3. Autophagic induction by both stressors increased
the abundance of fluorescent puncta formed by GFP-LC3, which could be blocked by 3-methyladenine. Significantly, such inhibition
of autophagy blocked cell death induced by H2O2 but not staurosporine. Suppression of Atg7 inhibited cell death by H2O2, but not staurosporine, whereas suppression of Beclin 1 prevented cell death by both treatments, suggesting it has a complex
role regulating both apoptosis and autophagy. We conclude that autophagic mechanisms are activated in an insult-dependent
manner and that H2O2 induces autophagic cell death. 相似文献
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Differential insult-dependent recruitment of the intrinsic mitochondrial pathway during neuronal programmed cell death 总被引:1,自引:1,他引:0
Diwakarla S Nagley P Hughes ML Chen B Beart PM 《Cellular and molecular life sciences : CMLS》2009,66(1):156-172
Programmed cell death contributes to neurological diseases and may involve mitochondrial dysfunction with redistribution of
apoptogenic proteins. We examined neuronal death to elucidate whether the intrinsic mitochondrial pathway and the crosstalk
between caspase-dependent/-independent injury was differentially recruited by stressors implicated in neurodegeneration. After
exposure of cultured cerebellar granule cells to various insults, the progression of injury was correlated with mitochondrial
involvement, including the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Injury
occurred across a continuum from Bax- and caspase-dependent (trophic- factor withdrawal) to Bax-independent, calpain-dependent
(excitotoxicity) injury. Trophic-factor withdrawal produced classical recruitment of the intrinsic pathway with activation
of caspase-3 and redistribution of cytochrome c, whereas excitotoxicity induced early redistribution of AIF and HtrA2/Omi,
elevation of intracellular calcium and mitochondrial depolarization. Patterns of engagement of neuronal programmed cell death
and the redistribution of mitochondrial IMS proteins were canonical, reflecting differential insult-dependencies.
Received 14 August 2008; received after revision 02 October 2008; accepted 23 October 2008 相似文献
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Cheung NS Choy MS Halliwell B Teo TS Bay BH Lee AY Qi RZ Koh VH Whiteman M Koay ES Chiu LL Zhu HJ Wong KP Beart PM Cheng HC 《Cellular and molecular life sciences : CMLS》2004,61(15):1926-1934
The tumor suppressor function of PTEN is attributed to its phospholipid phosphatase activity that
dephosphorylates the plasma membrane phosphatidylinositol-(3,4,5)-triphosphate
[PtdIns(3,4,5)P3]. Implicit in this notion is that PTEN needs to be targeted to the plasma
membrane to dephosphorylate PtdIns(3,4,5)P3. However, the recruitment of PTEN to the plasma
membrane is not fully understood. Here, we demonstrate PTEN accumulation in the detergent-insoluble fraction of
neuronal cells in response to treatment by the proteasome inhibitor lactacystin. First, lactacystin induces
apoptosis and the activation of caspase-3 in cultured cortical neurons. Second, PTEN undergoes proteolysis to
form a truncated 50-kDa form that lacks parts of its C-terminal tail. Third, the truncated PTEN is stably
associated with the detergent-insoluble fraction in which the plasma membrane marker protein flotillin-1 resides.
Taken together, our results suggest that truncation and accumulation of PTEN to the detergent-insoluble membrane
fraction are two events associated with the apoptotic signals of the proteasome inhibitor in cortical neurons.Received 24 March 2004; received after revision 26 May 2004; accepted 5 June 2004 相似文献
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