Role of endonuclease G in neuronal excitotoxicity in mice

Wu, Yongfei; Dong, Mei; Toepfer, Nicholas J.; Fan, Yunxia; Xu, Ming; Zhang, Jianhua

doi:10.1016/j.neulet.2004.04.093

Cited by 19 publications

(13 citation statements)

References 20 publications

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“…AIF has been shown to cause DNA fragmentation and chromatin condensation possibly in a cooperative manner with EndoG (62,63). These observations are consistent with previous reports (64,65) showing that focal cerebral ischemia induces nuclear translocation of AIF and that EndoG is involved in neuronal excitotoxicity using EndoG-deficient mice. The question then is how calpain activation leads to nuclear translocation of these mitochondria-derived DNA fragmentation factors.…”

Section: Fig 4 Expression and Activation Of Caspase-3 And Proteolyssupporting

confidence: 91%

Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains

Takano

Tomioka²,

Tsubuki³

et al. 2005

Journal of Biological Chemistry

170

153

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Calpain has been implicated in excitotoxic neurodegeneration, but its mechanism of action particularly in adult brains remains unclear. We generated mutant mice lacking or overexpressing calpastatin, the only solely calpain-specific inhibitor ever identified or synthesized. Modulation of calpastatin expression caused no defect in the mice under normal conditions, indicating that calpastatin functions as a negative regulator of calpain only under pathological conditions. Kainateevoked excitotoxicity in hippocampus resulted in proteolytic activation of a proapoptotic Bcl-2 subfamily member (Bid), nuclear translocation of mitochondriaderived DNA fragmentation factors (apoptosis-inducing factor and endonuclease G), DNA fragmentation, and nuclear condensation in pyramidal neurons. These apoptotic responses were significantly augmented by calpastatin deficiency. Consistently calpastatin overexpression suppressed them. No evidence of caspase-3 activation was detected. Our results demonstrated that calpain mediates excitotoxic signals through mobilization of proapoptotic factors in a caspase-independent manner. These mutant mice will serve as useful tools for investigating calpain involvement in various diseases.

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Section: Fig 4 Expression and Activation Of Caspase-3 And Proteolyssupporting

confidence: 91%

Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains

Takano

Tomioka²,

Tsubuki³

et al. 2005

Journal of Biological Chemistry

170

153

View full text Add to dashboard Cite

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“…In the latter instance, however, the endoG heterozygous mice were 129/Sv crossed with C57BL/6; the latter are resistant to KASE-induced neuronal death (Schauwecker and Steward, 1997), so this complicates interpretation of the protective effect of the hetereozygotes. The same authors showed that in wild-type mice endoG translocated to neuronal nuclei, but much later than in the current study, 5 days after KASE (Wu et al, 2004). In addition, calpastatin-deficient mice (calpastatin inactivates calpain) subjected to KASE showed cleavage of Bid as well as translocation of AIF and endoG from mitochondria to nuclei (Takano et al, 2005).…”

Section: Translocation Of Mitochondrial Proteinssupporting

confidence: 63%

“…Nuclear translocation of AIF has been reported following seizures (Heo et al, 2006;Wang et al, 2008), and endoG heterozygous mice had less kainic acid (KA) SE-induced neuronal death in hippocampus (Wu et al, 2004). In the latter instance, however, the endoG heterozygous mice were 129/Sv crossed with C57BL/6; the latter are resistant to KASE-induced neuronal death (Schauwecker and Steward, 1997), so this complicates interpretation of the protective effect of the hetereozygotes.…”

Section: Translocation Of Mitochondrial Proteinsmentioning

confidence: 99%

“…This is the first evidence of nuclear translocation of cath-B and cath-D, the first in vivo evidence of nuclear translocation of cyt c, and the first seizureinduced evidence of nuclear translocation of DNase II. EndoG has been shown to translocate to neuronal nuclei, but much later, 5 days after kainic acid-induced SE (Wu et al, 2004). The translocation in all cases was found in some neurons prior to cellular shrinkage and nuclear pyknosis, evidence of irreversible neuronal necrosis (Fujikawa, 1996;Fujikawa et al, 1999Fujikawa et al, , 2000aFujikawa et al, ,b, 2002Fujikawa et al, , 2007.…”

mentioning

confidence: 90%

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Nuclear translocation of mitochondrial cytochrome c, lysosomal cathepsins B and D, and three other death‐promoting proteins within the first 60 minutes of generalized seizures

Zhao

Aviles

Fujikawa

2010

J of Neuroscience Research

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We have shown that generalized seizures produce necrotic neurons with caspase-independent nuclear pyknosis and DNA fragmentation. In this study, we determined the time course of translocation of mitochondrial cytochrome c, apoptosis-inducing factor, endonuclease G, lysosomal cathepsins B and D, and DNase II with respect to signs of irreversible neuronal damage. Adult male Wistar rats underwent lithium-pilocarpine-induced seizures lasting for 60 min, 3 hr, and 3 hr with 6- or 24-hr survival periods, after which the brains were prepared for immunofluorescence microscopic examination of piriform cortex. Contrary to expectation, cytochrome c and cathepsins B and D translocated to neuronal nuclei with DNase II, endonuclease G, and apoptosis-inducing factor within 60 min of seizure onset and persisted for 24 hr after 3-hr seizures. After 60-min seizures, some neurons showed translocation of the death-promoting proteins in normal-appearing neurons, prior to their appearance in irreversibly damaged neurons. Western blots of subcellular fractions of cytochrome c and cathepsins B and D confirmed their nuclear translocation. This is the first evidence of nuclear translocation of cathepsins B and D and the first in vivo evidence of nuclear translocation of cytochrome c. The appearance of these mitochondrial proteins and lysosomal enzymes before signs of irreversible neuronal death suggests that they could contribute to seizure-induced nuclear pyknosis and DNA fragmentation.

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“…Although the mechanism for this reduction in latency is unknown, the rapidity of onset of seizures (11 min) makes it unlikely that DNA damage generated by the seizures is involved. This is supported by a recent study demonstrating that reduction of endonuclease G, an enzyme responsible for DNA cleavage during apoptosis, does not affect seizure susceptibility or kainate-induced behavioral responses, but reduces hippocampal cell death (Wu et al, 2004). Studies demonstrating that inhibition of GABAergic transmission reduces latency, whereas inhibition of AMPA/ kainate receptors prolongs latency, imply that latency duration is governed by the balance between excitatory and inhibitory circuitry (Gernert et al, 2002;Rubaj et al, 2003;Sinkkonen et al, 2004).…”

Section: Discussionmentioning

confidence: 73%

DNA damage and nonhomologous end joining in excitotoxicity: Neuroprotective role of DNA-PKcs in kainic acid-induced seizures

et al. 2005

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DNA repair plays a critical, but imprecisely defined role in excitotoxic injury and neuronal survival throughout adulthood. We utilized an excitotoxic injury model to compare the location and phenotype of degenerating neurons in mice (strain 129-C57BL) deficient in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), an enzyme required for nonhomologous end joining (NHEJ). Brains from untreated adult heterozygous and DNA-PKcs null mice displayed comparable cytoarchitecture and undetectable levels of cell death. By day 1, and extending through 4 days following kainic acid-induced seizures, brains from DNA-PKcs null mice showed widespread neurodegeneration that encompassed the entire hippocampal CA1-CA3 pyramidal cell layer, entorhinal cortex, and lateral septum, with relative sparing of the dentate gyrus granule cell layer and hilus, as judged by toluidine blue, Fluoro-Jade B, and terminal dUTP nick end labeling staining. In contrast, seizure-related neurodegeneration in heterozygous littermates was limited to the CA3 region of the hippocampus. NeuN and calbindin staining revealed a selective decrease in the number and density of NeuN-positive neurons in the pyramidal layers of degenerating regions in both heterozygous and DNA-PKcs null mice. To elucidate the mechanisms leading to cell death, we examined an involvement of the p53 pathway, known to be induced by DNA damage. Addition of pifithrin-alpha, a p53 inhibitor, or expression of a dominant-negative p53 rescued neurons from kainate-induced excitotoxic cell death in primary cortical cultures derived from wildtype, DNA-PKcs heterozygous, or DNA-PKcs null neonatal mice. Moreover, pifithrin-alpha prevented kainate-induced loss of mitochondrial membrane potential, dendrite degeneration, and cell death. Results suggest that NHEJ plays a neuroprotective role in excitotoxicity, within the perforant, Schaffer collateral, hippocampal-septal, and temperoammonic pathways, in part by repairing DNA damage that would otherwise result in activation of a p53-dependent apoptotic cascade.

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Role of endonuclease G in neuronal excitotoxicity in mice

Cited by 19 publications

References 20 publications

Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains

Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains

Nuclear translocation of mitochondrial cytochrome c, lysosomal cathepsins B and D, and three other death‐promoting proteins within the first 60 minutes of generalized seizures

DNA damage and nonhomologous end joining in excitotoxicity: Neuroprotective role of DNA-PKcs in kainic acid-induced seizures

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