NF-κB/p53信号通路在谷氨酸受体介导的自噬激活和细胞凋亡中的作用
|
摘要
目的:研究核因子-κB (Nuclear Factor-kappa B, NF-κB)/p53信号通路在谷氨酸受体介导的神经兴奋性毒性中的作用及机制。
方法:采用脑立体定位纹状体内给药法,建立谷氨酸受体介导的大鼠神经兴奋性毒性的体内模型,RT-PCR和Western Blot检测喹啉酸(Quinolinic acid, QA)引起的凋亡相关蛋白——p53、PUMA、Bax、Bcl-2和自噬相关蛋白——DRAM (damage-regulated autophagy modulator)、LC3 (microtubule-associated protein 1 light chain 3)、Beclin1的mRNA和蛋白表达的变化。DNA ladder及尼氏染色法观察NF-κB抑制剂SN50和p53抑制剂PFT-α(Pifithrin-alpha)对模型大鼠纹状体神经元的保护作用;RT-PCR和Western Blot检测SN50和PFT-α对模型大鼠纹状体内凋亡相关蛋白p53、PUMA (p53 up-regulate modulator of apoptosis)、Bax、Bcl-2和自噬相关蛋白DRAM、LC3、Beclin1的mRNA和蛋白表达的影响。尼氏染色法观察Cathepsin L抑制剂Z-FY-DMK对模型大鼠纹状体神经元的保护作用;免疫组织化学法检测Z-FY-DMK对模型大鼠纹状体内NF-κB激活的影响;Western Blot检测Z-FY-DMK对模型大鼠纹状体内IκBα(inhibitor of NF-kB, alpha isoform)、p-IκBα(phospho-IκB alpha)、自噬相关蛋白DRAM、Beclin1、P62蛋白表达的影响。采用谷氨酸处理原代培养的大鼠胎鼠纹状体神经元,建立谷氨酸受体介导的神经兴奋性毒性的体外模型,LDH法检测SN50、PFT-α、Z-FY-DMK对神经元存活率的影响;免疫细胞化学法检测SN50和PFT-α对谷氨酸引起的线粒体膜电位的影响;Western Blot检测Z-FY-DMK对兴奋性毒性细胞模型中自噬相关蛋白Beclin1和P62蛋白表达的影响。
结果:本实验成功建立了大鼠神经兴奋性毒性的体内模型。RT-PCR和Western Blot结果显示,模型大鼠纹状体内p53、PUMA、Bax表达增加,Bcl-2表达降低和DRAM、LC3、Beclin1表达上调。SN50、PFT-α给药组与模型组相比,DNA ladder凋亡条带明显减弱,损伤面积显著减小(p<0.01);RT-PCR和Western Blot结果显示SN50和PFT-α可对抗QA模型大鼠纹状体中p53、PUMA、Bax上调、Bcl-2下调、DRAM、LC3、Beclin1上调。Z-FY-DMK给药组与模型组相比,损伤面积显著减小(p<0.01);免疫组化结果显示Z-FY-DMK可抑制QA模型大鼠纹状体内NF-κB的核转位;Western Blot结果显示Z-FY-DMK可对抗QA模型大鼠纹状体中IκBα降解和磷酸化、以及DRAM、Beclin1上调和P62的下调。本实验成功建立了大鼠胎鼠的原代纹状体神经元兴奋性毒性的体外模型。LDH法结果显示SN50、PFT-α、Z-FY-DMK可减少谷氨酸引起的神经元死亡;免疫细胞化学法结果显示SN50和PFT-α可抑制谷氨酸受体介导的线粒体膜电位下降;Western Blot结果显示Z-FY-DMK可对抗谷氨酸引起的Beclin1和P62蛋白表达的变化。
结论:谷氨酸受体介导的神经兴奋性毒性中,NF-κB抑制剂和p53抑制剂通过影响NF-κB/p53信号通路,抑制神经元自噬和凋亡的发生;Cathepsin L抑制剂Z-FY-DMK通过抑制谷氨酸受体介导的IκBα降解和磷酸化、NF-κB核转位、自噬激活,最终阻断NF-κB/p53信号通路,从而对谷氨酸受体激活引起的纹状体神经元损伤起保护作用。
Aim: To study the roles of Nuclear Factor-kappa B (NF-κB)/p53 pathway in autophagy and apoptosis mediated by glutamate receptors.
Methods: The in vivo excitotoxic model was produced with stereotaxic administration of Quinolinic acid (QA) into unilateral striatum. The changes in the expression of p53 and its target genes involved in apoptosis and autophagy including PUMA, Bax, Bcl-2, damage-regulated autophagy modulator (DRAM), and other autophagic proteins including microtubule-associated protein 1 light chain 3 (LC3), and beclin1 were assessed with RT-PCR and Western blot analysis. The neuroprotective effects of the NF-κB inhibitor SN50 and the p53 inhibitor Pifithrin-alpha (PFT-α) were assessed with internucleosomal DNA fragmentation and Cresyl violet staining. Effects of SN50 or PFT-αon QA-induced increases in the level of p53, PUMA, Bax, decreases in the level of Bcl-2, and increases in the level of DRAM, LC3, Beclin1 were detected with RT-PCR and Western blot analysis. The neuroprotective effects of the Cathepsin L inhibitor Z-FY-DMK were assessed with Cresyl violet staining. Effects of Z-FY-DMK on QA-induced NF-κB activation were detected with immunohistochemical analysis. Effects of Z-FY-DMK on QA-induced IκBαdegradation and phosphorylation, changes in the levels of DRAM, Beclin1, P62 were detected with Western blot analysis. The in vitro excitotoxic model was produced with glutamate treatment of primary striatum neurons. The neuroprotective effects of SN50, PFT-αand Z-FY-DMK were assessed with LDH. Effects of SN50 and PFT-αon glutamate-induced decrease of mitochondrial transmembrane potential were assessed with immunofluorescence analysis. Effects of Z-FY-DMK on glutamate-induced changes of protein levels of Beclin1 and P62 were observed using Western blot analysis.
Results: We have successfully established in vivo model of excitotoxicity by QA. QA induced increases in the expression of p53, PUMA, Bax and a decrease in Bcl-2. QA also upregulated DRAM, the ratio of LC3-II/LC3-I and the levels of Beclin1. QA- induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by SN50 or PFT-α(p<0.01). SN50 and PFT-αreversed QA-induced increases in the expression of p53, PUMA, Bax, decrease in Bcl-2, and up-regulation of DRAM, the ratio of LC3-II/LC3-I and the levels Beclin1 in the striatum. QA-induced loss of striatal neurons were robustly inhibited by Z-FY-DMK (p<0.01). Z-FY-DMK reversed QA-induced activation of NF-κB. Z-FY-DMK inhibited QA-induced IκBαdegradation and phosphorylation, up-regulation of DRAM, Beclin1, and down-ragulation of P62. We have successfully established the in vitro excitotoxic model with glutamate in cultured primary striatal neurons. LDH tests showed that the damage of neurons induced by excitotoxicity was significantly depressed by the treatment with SN50, PFT-αand Z-FY-DMK. Immunofluorecsence analysis showed that glutamate-induced depolarization of mitochondrial membrane was attenuated by SN50 and PFT-α. Western blot analysis showed that glutamate-induced Beclin1 upragulation and P62 downregulation were attenuated by Z-FY-DMK.
Conclusions: These results suggest that over-stimulation of glutamate receptors can induce NF-κB-dependent expression of p53. NF-κB/p53 pathway participates in excitotoxic neuronal death through both apoptotic and autophagic mechanisms. Cathepsin L inhibitor has neuroprotective effects by inhibiting glutamate receptors-induced IκBαdegradation and phosphorylation, NF-κB nuclear translocation and activation of autophagy.
方法:采用脑立体定位纹状体内给药法,建立谷氨酸受体介导的大鼠神经兴奋性毒性的体内模型,RT-PCR和Western Blot检测喹啉酸(Quinolinic acid, QA)引起的凋亡相关蛋白——p53、PUMA、Bax、Bcl-2和自噬相关蛋白——DRAM (damage-regulated autophagy modulator)、LC3 (microtubule-associated protein 1 light chain 3)、Beclin1的mRNA和蛋白表达的变化。DNA ladder及尼氏染色法观察NF-κB抑制剂SN50和p53抑制剂PFT-α(Pifithrin-alpha)对模型大鼠纹状体神经元的保护作用;RT-PCR和Western Blot检测SN50和PFT-α对模型大鼠纹状体内凋亡相关蛋白p53、PUMA (p53 up-regulate modulator of apoptosis)、Bax、Bcl-2和自噬相关蛋白DRAM、LC3、Beclin1的mRNA和蛋白表达的影响。尼氏染色法观察Cathepsin L抑制剂Z-FY-DMK对模型大鼠纹状体神经元的保护作用;免疫组织化学法检测Z-FY-DMK对模型大鼠纹状体内NF-κB激活的影响;Western Blot检测Z-FY-DMK对模型大鼠纹状体内IκBα(inhibitor of NF-kB, alpha isoform)、p-IκBα(phospho-IκB alpha)、自噬相关蛋白DRAM、Beclin1、P62蛋白表达的影响。采用谷氨酸处理原代培养的大鼠胎鼠纹状体神经元,建立谷氨酸受体介导的神经兴奋性毒性的体外模型,LDH法检测SN50、PFT-α、Z-FY-DMK对神经元存活率的影响;免疫细胞化学法检测SN50和PFT-α对谷氨酸引起的线粒体膜电位的影响;Western Blot检测Z-FY-DMK对兴奋性毒性细胞模型中自噬相关蛋白Beclin1和P62蛋白表达的影响。
结果:本实验成功建立了大鼠神经兴奋性毒性的体内模型。RT-PCR和Western Blot结果显示,模型大鼠纹状体内p53、PUMA、Bax表达增加,Bcl-2表达降低和DRAM、LC3、Beclin1表达上调。SN50、PFT-α给药组与模型组相比,DNA ladder凋亡条带明显减弱,损伤面积显著减小(p<0.01);RT-PCR和Western Blot结果显示SN50和PFT-α可对抗QA模型大鼠纹状体中p53、PUMA、Bax上调、Bcl-2下调、DRAM、LC3、Beclin1上调。Z-FY-DMK给药组与模型组相比,损伤面积显著减小(p<0.01);免疫组化结果显示Z-FY-DMK可抑制QA模型大鼠纹状体内NF-κB的核转位;Western Blot结果显示Z-FY-DMK可对抗QA模型大鼠纹状体中IκBα降解和磷酸化、以及DRAM、Beclin1上调和P62的下调。本实验成功建立了大鼠胎鼠的原代纹状体神经元兴奋性毒性的体外模型。LDH法结果显示SN50、PFT-α、Z-FY-DMK可减少谷氨酸引起的神经元死亡;免疫细胞化学法结果显示SN50和PFT-α可抑制谷氨酸受体介导的线粒体膜电位下降;Western Blot结果显示Z-FY-DMK可对抗谷氨酸引起的Beclin1和P62蛋白表达的变化。
结论:谷氨酸受体介导的神经兴奋性毒性中,NF-κB抑制剂和p53抑制剂通过影响NF-κB/p53信号通路,抑制神经元自噬和凋亡的发生;Cathepsin L抑制剂Z-FY-DMK通过抑制谷氨酸受体介导的IκBα降解和磷酸化、NF-κB核转位、自噬激活,最终阻断NF-κB/p53信号通路,从而对谷氨酸受体激活引起的纹状体神经元损伤起保护作用。
Aim: To study the roles of Nuclear Factor-kappa B (NF-κB)/p53 pathway in autophagy and apoptosis mediated by glutamate receptors.
Methods: The in vivo excitotoxic model was produced with stereotaxic administration of Quinolinic acid (QA) into unilateral striatum. The changes in the expression of p53 and its target genes involved in apoptosis and autophagy including PUMA, Bax, Bcl-2, damage-regulated autophagy modulator (DRAM), and other autophagic proteins including microtubule-associated protein 1 light chain 3 (LC3), and beclin1 were assessed with RT-PCR and Western blot analysis. The neuroprotective effects of the NF-κB inhibitor SN50 and the p53 inhibitor Pifithrin-alpha (PFT-α) were assessed with internucleosomal DNA fragmentation and Cresyl violet staining. Effects of SN50 or PFT-αon QA-induced increases in the level of p53, PUMA, Bax, decreases in the level of Bcl-2, and increases in the level of DRAM, LC3, Beclin1 were detected with RT-PCR and Western blot analysis. The neuroprotective effects of the Cathepsin L inhibitor Z-FY-DMK were assessed with Cresyl violet staining. Effects of Z-FY-DMK on QA-induced NF-κB activation were detected with immunohistochemical analysis. Effects of Z-FY-DMK on QA-induced IκBαdegradation and phosphorylation, changes in the levels of DRAM, Beclin1, P62 were detected with Western blot analysis. The in vitro excitotoxic model was produced with glutamate treatment of primary striatum neurons. The neuroprotective effects of SN50, PFT-αand Z-FY-DMK were assessed with LDH. Effects of SN50 and PFT-αon glutamate-induced decrease of mitochondrial transmembrane potential were assessed with immunofluorescence analysis. Effects of Z-FY-DMK on glutamate-induced changes of protein levels of Beclin1 and P62 were observed using Western blot analysis.
Results: We have successfully established in vivo model of excitotoxicity by QA. QA induced increases in the expression of p53, PUMA, Bax and a decrease in Bcl-2. QA also upregulated DRAM, the ratio of LC3-II/LC3-I and the levels of Beclin1. QA- induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by SN50 or PFT-α(p<0.01). SN50 and PFT-αreversed QA-induced increases in the expression of p53, PUMA, Bax, decrease in Bcl-2, and up-regulation of DRAM, the ratio of LC3-II/LC3-I and the levels Beclin1 in the striatum. QA-induced loss of striatal neurons were robustly inhibited by Z-FY-DMK (p<0.01). Z-FY-DMK reversed QA-induced activation of NF-κB. Z-FY-DMK inhibited QA-induced IκBαdegradation and phosphorylation, up-regulation of DRAM, Beclin1, and down-ragulation of P62. We have successfully established the in vitro excitotoxic model with glutamate in cultured primary striatal neurons. LDH tests showed that the damage of neurons induced by excitotoxicity was significantly depressed by the treatment with SN50, PFT-αand Z-FY-DMK. Immunofluorecsence analysis showed that glutamate-induced depolarization of mitochondrial membrane was attenuated by SN50 and PFT-α. Western blot analysis showed that glutamate-induced Beclin1 upragulation and P62 downregulation were attenuated by Z-FY-DMK.
Conclusions: These results suggest that over-stimulation of glutamate receptors can induce NF-κB-dependent expression of p53. NF-κB/p53 pathway participates in excitotoxic neuronal death through both apoptotic and autophagic mechanisms. Cathepsin L inhibitor has neuroprotective effects by inhibiting glutamate receptors-induced IκBαdegradation and phosphorylation, NF-κB nuclear translocation and activation of autophagy.
引文
1. Chandra V, Pandav R, Dodge HH, Johnston JM, Belle SH, DeKosky ST, Ganguli M. Incidence of Alzheimer's disease in a rural community in India: the Indo-US study. Neurology. 2001;57(6):985-989.
2. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1(8):623-634.
3. Greenamyre JT, Porter RH. Anatomy and physiology of glutamate in the CNS. Neurology. 1994;44(11 Suppl 8):S7-13.
4. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994;330(9):613-622.
5. van den Pol AN, Wuarin JP, Dudek FE. Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science. 1990;250(4985):1276-1278.
6. Koutsilieri E, Riederer P. Excitotoxicity and new antiglutamatergic strategies in Parkinson's disease and Alzheimer's disease. Parkinsonism Relat Disord. 2007;13 Suppl 3:S329-331.
7. Cowan CM, Fan MM, Fan J, Shehadeh J, Zhang LY, Graham RK, Hayden MR, Raymond LA. Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity. J Neurosci. 2008;28(48):12725-12735.
8. Rodriguez MJ, Bernal F, Andres N, Malpesa Y, Mahy N. Excitatory amino acids and neurodegeneration: a hypothetical role of calcium precipitation. Int J Dev Neurosci. 2000;18(2-3):299-307.
9. Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis. 2010 Mar 6.
10. Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry. 1998;155(6):726-732.
11. Olney JW, Wozniak DF, Farber NB. Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch Neurol. 1997;54(10):1234-1240.
12. Whetsell WO, Jr., Shapira NA. Neuroexcitation, excitotoxicity and human neurological disease. Lab Invest. 1993;68(4):372-387.
13. Olney JW. Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry. 1989;26(5):505-525.
14. Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol. 1981;72(4):411-412.
15. Greenamyre JT, Maragos WF, Albin RL, Penney JB, Young AB. Glutamate transmission and toxicity in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12(4):421-430.
16. Dunnett SB, Svendsen CN. Huntington's disease: animal models and transplantation repair. Curr Opin Neurobiol. 1993;3(5):790-796.
17. Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron. 2002;33(6):849-860.
18. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304(5676):1500-1502.
19. Estrada Sanchez AM, Mejia-Toiber J, Massieu L. Excitotoxic neuronal death and the pathogenesis of Huntington's disease. Arch Med Res. 2008;39(3):265-276.
20. Liang ZQ, Wang XX, Wang Y, Chuang DM, DiFiglia M, Chase TN, Qin ZH. Susceptibility of striatal neurons to excitotoxic injury correlates with basal levels of Bcl-2 and the induction of p53 and c-Myc immunoreactivity. Neurobiol Dis. 2005;20(2):562-573.
21. Nakai M, Qin ZH, Chen JF, Wang Y, Chase TN. Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. J Neurochem. 2000;74(2):647-658.
22. Qin ZH, Wang Y, Chase TN. Stimulation of N-methyl-D-aspartate receptors induces apoptosis in rat brain. Brain Res. 1996;725(2):166-176.
23. Cao Y, Gu ZL, Lin F, Han R, Qin ZH. Caspase-1 inhibitor Ac-YVAD-CHO attenuates quinolinic acid-induced increases in p53 and apoptosis in rat striatum. Acta Pharmacol Sin. 2005;26(2):150-154.
24. Liang ZQ, Wang X, Li LY, Wang Y, Chen RW, Chuang DM, Chase TN, Qin ZH. Nuclear factor-kappaB-dependent cyclin D1 induction and DNA replication associated with N-methyl-D-aspartate receptor-mediated apoptosis in rat striatum. J Neurosci Res. 2007;85(6):1295-1309.
25. Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 2001;8(6):569-581.
26. Shacka JJ, Lu J, Xie ZL, Uchiyama Y, Roth KA, Zhang J. Kainic acid induces early and transient autophagic stress in mouse hippocampus. Neurosci Lett. 2007;414(1):57-60.
27. Yue Z, Wang QJ, Komatsu M. Neuronal autophagy: going the distance to the axon. Autophagy. 2008;4(1):94-96.
28. Wang Y, Han R, Liang ZQ, Wu JC, Zhang XD, Gu ZL, Qin ZH. An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid. Autophagy. 2008;4(2):214-226.
29. Wang Y, Gu ZL, Cao Y, Liang ZQ, Han R, Bennett MC, Qin ZH. Lysosomal enzyme cathepsin B is involved in kainic acid-induced excitotoxicity in rat striatum. Brain Res. 2006;1071(1):245-249.
30. Lockshin RA, Zakeri Z. Apoptosis, autophagy, and more. Int J Biochem Cell Biol. 2004;36(12):2405-2419.
31. Klionsky DJ. Cell biology: regulated self-cannibalism. Nature. 2004;431(7004):31-32.
32. Klionsky DJ, Cregg JM, Dunn WA, Jr., Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y. A unified nomenclature for yeast autophagy-related genes. Dev Cell. 2003;5(4):539-545.
33. Monastyrska I, Klionsky DJ. Autophagy in organelle homeostasis: peroxisome turnover. Mol Aspects Med. 2006;27(5-6):483-494.
34. Kaushik S, Cuervo AM. Autophagy as a cell-repair mechanism: activation of chaperone-mediated autophagy during oxidative stress. Mol Aspects Med. 2006;27(5-6):444-454.
35. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6(4):463-477.
36. Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc Natl Acad Sci U S A. 2004;101(10):3438-3443.
37. Lee CY, Baehrecke EH. Steroid regulation of autophagic programmed cell death during development. Development. 2001;128(8):1443-1455.
38. Rodriguez-Enriquez S, He L, Lemasters JJ. Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol. 2004;36(12):2463-2472.
39. Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol. 2002;157(3):455-468.
40. Lipinski MM, Yuan J. Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol. 2004;4(1):85-90.
41. Venkatraman P, Wetzel R, Tanaka M, Nukina N, Goldberg AL. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell. 2004;14(1):95-104.
42. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278(27):25009-25013.
43. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585-595.
44. Yuan J, Lipinski M, Degterev A. Diversity in the mechanisms of neuronal cell death. Neuron. 2003;40(2):401-413.
45. Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N. A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron. 2002;35(5):921-933.
46. Cataldo AM, Barnett JL, Pieroni C, Nixon RA. Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci. 1997;17(16):6142-6151.
47. Fortun J, Dunn WA, Jr., Joy S, Li J, Notterpek L. Emerging role for autophagy in the removal of aggresomes in Schwann cells. J Neurosci. 2003;23(33):10672-10680.
48. Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283(46):31315-31322.
49. Sha D, Chin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet. 2010;19(2):352-363.
50. Gorbacheva L, Pinelis V, Ishiwata S, Strukova S, Reiser G. Activated protein C prevents glutamate- and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons. Neuroscience. 2010;165(4):1138-1146.
51. Nijboer CH, Heijnen CJ, Groenendaal F, May MJ, van Bel F, Kavelaars A. A dual role of the NF-kappaB pathway in neonatal hypoxic-ischemic brain damage. Stroke. 2008;39(9):2578-2586.
52. Qin ZH, Tao LY, Chen X. Dual roles of NF-kappaB in cell survival and implications of NF-kappaB inhibitors in neuroprotective therapy. Acta Pharmacol Sin. 2007;28(12):1859-1872.
53. Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Kohrmann M, Potrovita I, Maegele I, Beyer C, Burke JR, Hasan MT, Bujard H, Wirth T,Pasparakis M, Schwaninger M. IKK mediates ischemia-induced neuronal death. Nat Med. 2005;11(12):1322-1329.
54. Huang CY, Fujimura M, Noshita N, Chang YY, Chan PH. SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21(2):163-173.
55. Bui NT, Livolsi A, Peyron JF, Prehn JH. Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha. J Cell Biol. 2001;152(4):753-764.
56. Zhang XD, Wang Y, Zhang X, Han R, Wu JC, Liang ZQ, Gu ZL, Han F, Fukunaga K, Qin ZH. p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum. Autophagy. 2009;5(3):339-350.
57. Kim R, Emi M, Tanabe K. Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol. 2006;57(5):545-553.
58. Lemasters JJ. Modulation of mitochondrial membrane permeability in pathogenesis, autophagy and control of metabolism. J Gastroenterol Hepatol. 2007;22 Suppl 1:S31-37.
59. Chen Y, Gibson SB. Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy. 2008;4(2):246-248.
60. Moreira PI, Santos MS, Oliveira CR. Alzheimer's disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal. 2007;9(10):1621-1630.
61. Yan CH, Yang YP, Qin ZH, Gu ZL, Reid P, Liang ZQ. Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells. Acta Pharmacol Sin. 2007;28(4):540-548.
62. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126(1):121-134.
63. Crighton D, Wilkinson S, Ryan KM. DRAM links autophagy to p53 and programmed cell death. Autophagy. 2007;3(1):72-74.
64. Dolga AM, Granic I, Blank T, Knaus HG, Spiess J, Luiten PG, Eisel UL, Nijholt IM. TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappaB-dependent up-regulation of K2.2 channels. J Neurochem. 2008;107(4):1158-1167.
65. Lebrun-Julien F, Duplan L, Pernet V, Osswald I, Sapieha P, Bourgeois P, Dickson K, Bowie D, Barker PA, Di Polo A. Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism. J Neurosci. 2009;29(17):5536-5545.
66. Qin ZH, Wang Y, Chen RW, Wang X, Ren M, Chuang DM, Chase TN. Prostaglandin A(1) protects striatal neurons against excitotoxic injury in rat striatum. J Pharmacol Exp Ther. 2001;297(1):78-87.
67. Shumway SD, Miyamoto S. A mechanistic insight into a proteasome-independent constitutive inhibitor kappaBalpha (IkappaBalpha) degradation and nuclear factor kappaB (NF-kappaB) activation pathway in WEHI-231 B-cells. Biochem J. 2004;380(Pt 1):173-180.
68. Hook VY. Unique neuronal functions of cathepsin L and cathepsin B in secretory vesicles: biosynthesis of peptides in neurotransmission and neurodegenerative disease. Biol Chem. 2006;387(10-11):1429-1439.
69. Fei XF, Qin ZH, Xiang B, Li LY, Han F, Fukunaga K, Liang ZQ. Olomoucine inhibits cathepsin L nuclear translocation, activates autophagy and attenuates toxicity of 6-hydroxydopamine. Brain Res. 2009;1264:85-97.
70. Bankstahl JP, Hoffmann K, Bethmann K, Loscher W. Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. Neuropharmacology. 2008;54(6):1006-1016.
71. Maier C, Dertwinkel R, Mansourian N, Hosbach I, Schwenkreis P, Senne I, Skipka G, Zenz M, Tegenthoff M. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain--results of a randomized double-blinded, placebo-controlled trial. Pain. 2003;103(3):277-283.
72. Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci. 1999;19(10):4023-4033.
73. Qin ZH, Wang Y, Nakai M, Chase TN. Nuclear factor-kappa B contributes to excitotoxin-induced apoptosis in rat striatum. Mol Pharmacol. 1998;53(1):33-42.
74. Wang Y, Dong XX, Cao Y, Liang ZQ, Han R, Wu JC, Gu ZL, Qin ZH. p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms. Eur J Neurosci. 2009;30(12):2258-2270.
75. Liang ZQ, Li YL, Zhao XL, Han R, Wang XX, Wang Y, Chase TN, Bennett MC, Qin ZH. NF-kappaB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. Brain Res. 2007;1145:190-203.
76. Rossi F, Cattaneo E. Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci. 2002;3(5):401-409.
77. Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol. 1999;144(5):891-901.
78. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9(6):1799-1805.
79. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19(21):5720-5728.
80. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672-676.
81. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100(25):15077-15082.
82. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, Gudkov AV. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science. 1999;285(5434):1733-1737.
83. Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, Greig NH, Mattson MP. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem. 2001;77(1):220-228.
84. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press; 1998.
85. Gal J, Strom AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, Zhu H. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem. 2009;111(4):1062-1073.
86. Yue Z. Regulation of neuronal autophagy in axon: implication of autophagy in axonal function and dysfunction/degeneration. Autophagy. 2007;3(2):139-141.
87. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181-197.
88. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282(33):24131-24145.
89. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290(5497):1717-1721.
90. Akdemir F, Farkas R, Chen P, Juhasz G, Medved'ova L, Sass M, Wang L, Wang X, Chittaranjan S, Gorski SM, Rodriguez A, Abrams JM. Autophagy occurs upstream or parallel to the apoptosome during histolytic cell death. Development. 2006;133(8):1457-1465.
91. Shacka JJ, Klocke BJ, Shibata M, Uchiyama Y, Datta G, Schmidt RE, Roth KA. Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons. Mol Pharmacol. 2006;69(4):1125-1136.
92. Yan CH, Liang ZQ, Gu ZL, Yang YP, Reid P, Qin ZH. Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon. 2006;47(5):521-530.
93. Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L, Tolkovsky A. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 2005;1(1):11-22.
94. Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN, McKinnon PJ, Cleveland JL, Zambetti GP. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell. 2003;4(4):321-328.
95. Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan P, Drummond-Main C, Poulter MO, Ferguson SS, Strasser A, Cregan SP. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci. 2007;27(47):12989-12999.
96. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303(5660):1010-1014.
97. Lahiry L, Saha B, Chakraborty J, Bhattacharyya S, Chattopadhyay S, Banerjee S, Choudhuri T, Mandal D, Bhattacharyya A, Sa G, Das T. Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis. Apoptosis. 2008;13(6):771-781.
98. Gaytan M, Morales C, Sanchez-Criado JE, Gaytan F. Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum. Cell Tissue Res. 2008;331(2):509-517.
99. Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD, Han F, Fukunaga K, Qin ZH. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy. 2008;4(6):762-769.
100. Kamada Y, Sekito T, Ohsumi Y. Autophagy in yeast: a TOR-mediated response to nutrient starvation. Curr Top Microbiol Immunol. 2004;279:73-84.
101. Komarova EA, Neznanov N, Komarov PG, Chernov MV, Wang K, Gudkov AV. p53 inhibitor pifithrin alpha can suppress heat shock and glucocorticoid signaling pathways. J Biol Chem. 2003;278(18):15465-15468.
102. Strom E, Sathe S, Komarov PG, Chernova OB, Pavlovska I, Shyshynova I, Bosykh DA, Burdelya LG, Macklis RM, Skaliter R, Komarova EA, Gudkov AV. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat Chem Biol. 2006;2(9):474-479.
103. Green DR, Chipuk JE. p53 and metabolism: Inside the TIGAR. Cell. 2006;126(1):30-32.
104. Sohn D, Graupner V, Neise D, Essmann F, Schulze-Osthoff K, Janicke RU. Pifithrin-alpha protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53. Cell Death Differ. 2009;16(6):869-878.
105. Liberski PP, Sikorska B, Bratosiewicz-Wasik J, Gajdusek DC, Brown P. Neuronal cell death in transmissible spongiform encephalopathies (prion diseases) revisited: from apoptosis to autophagy. Int J Biochem Cell Biol. 2004;36(12):2473-2490.
106. Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5(11):886-897.
107. Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y, Schulz-Schaeffer W, Watanabe T, Waguri S, Kametaka S, Shibata M, Yamamoto K, Kominami E, Peters C, von Figura K, Uchiyama Y. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci. 2000;20(18):6898-6906.
108. Kim YJ, Sapp E, Cuiffo BG, Sobin L, Yoder J, Kegel KB, Qin ZH, Detloff P, Aronin N, DiFiglia M. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis. 2006;22(2):346-356.
2. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1(8):623-634.
3. Greenamyre JT, Porter RH. Anatomy and physiology of glutamate in the CNS. Neurology. 1994;44(11 Suppl 8):S7-13.
4. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994;330(9):613-622.
5. van den Pol AN, Wuarin JP, Dudek FE. Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science. 1990;250(4985):1276-1278.
6. Koutsilieri E, Riederer P. Excitotoxicity and new antiglutamatergic strategies in Parkinson's disease and Alzheimer's disease. Parkinsonism Relat Disord. 2007;13 Suppl 3:S329-331.
7. Cowan CM, Fan MM, Fan J, Shehadeh J, Zhang LY, Graham RK, Hayden MR, Raymond LA. Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity. J Neurosci. 2008;28(48):12725-12735.
8. Rodriguez MJ, Bernal F, Andres N, Malpesa Y, Mahy N. Excitatory amino acids and neurodegeneration: a hypothetical role of calcium precipitation. Int J Dev Neurosci. 2000;18(2-3):299-307.
9. Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis. 2010 Mar 6.
10. Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry. 1998;155(6):726-732.
11. Olney JW, Wozniak DF, Farber NB. Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch Neurol. 1997;54(10):1234-1240.
12. Whetsell WO, Jr., Shapira NA. Neuroexcitation, excitotoxicity and human neurological disease. Lab Invest. 1993;68(4):372-387.
13. Olney JW. Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry. 1989;26(5):505-525.
14. Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol. 1981;72(4):411-412.
15. Greenamyre JT, Maragos WF, Albin RL, Penney JB, Young AB. Glutamate transmission and toxicity in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12(4):421-430.
16. Dunnett SB, Svendsen CN. Huntington's disease: animal models and transplantation repair. Curr Opin Neurobiol. 1993;3(5):790-796.
17. Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron. 2002;33(6):849-860.
18. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304(5676):1500-1502.
19. Estrada Sanchez AM, Mejia-Toiber J, Massieu L. Excitotoxic neuronal death and the pathogenesis of Huntington's disease. Arch Med Res. 2008;39(3):265-276.
20. Liang ZQ, Wang XX, Wang Y, Chuang DM, DiFiglia M, Chase TN, Qin ZH. Susceptibility of striatal neurons to excitotoxic injury correlates with basal levels of Bcl-2 and the induction of p53 and c-Myc immunoreactivity. Neurobiol Dis. 2005;20(2):562-573.
21. Nakai M, Qin ZH, Chen JF, Wang Y, Chase TN. Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. J Neurochem. 2000;74(2):647-658.
22. Qin ZH, Wang Y, Chase TN. Stimulation of N-methyl-D-aspartate receptors induces apoptosis in rat brain. Brain Res. 1996;725(2):166-176.
23. Cao Y, Gu ZL, Lin F, Han R, Qin ZH. Caspase-1 inhibitor Ac-YVAD-CHO attenuates quinolinic acid-induced increases in p53 and apoptosis in rat striatum. Acta Pharmacol Sin. 2005;26(2):150-154.
24. Liang ZQ, Wang X, Li LY, Wang Y, Chen RW, Chuang DM, Chase TN, Qin ZH. Nuclear factor-kappaB-dependent cyclin D1 induction and DNA replication associated with N-methyl-D-aspartate receptor-mediated apoptosis in rat striatum. J Neurosci Res. 2007;85(6):1295-1309.
25. Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 2001;8(6):569-581.
26. Shacka JJ, Lu J, Xie ZL, Uchiyama Y, Roth KA, Zhang J. Kainic acid induces early and transient autophagic stress in mouse hippocampus. Neurosci Lett. 2007;414(1):57-60.
27. Yue Z, Wang QJ, Komatsu M. Neuronal autophagy: going the distance to the axon. Autophagy. 2008;4(1):94-96.
28. Wang Y, Han R, Liang ZQ, Wu JC, Zhang XD, Gu ZL, Qin ZH. An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid. Autophagy. 2008;4(2):214-226.
29. Wang Y, Gu ZL, Cao Y, Liang ZQ, Han R, Bennett MC, Qin ZH. Lysosomal enzyme cathepsin B is involved in kainic acid-induced excitotoxicity in rat striatum. Brain Res. 2006;1071(1):245-249.
30. Lockshin RA, Zakeri Z. Apoptosis, autophagy, and more. Int J Biochem Cell Biol. 2004;36(12):2405-2419.
31. Klionsky DJ. Cell biology: regulated self-cannibalism. Nature. 2004;431(7004):31-32.
32. Klionsky DJ, Cregg JM, Dunn WA, Jr., Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y. A unified nomenclature for yeast autophagy-related genes. Dev Cell. 2003;5(4):539-545.
33. Monastyrska I, Klionsky DJ. Autophagy in organelle homeostasis: peroxisome turnover. Mol Aspects Med. 2006;27(5-6):483-494.
34. Kaushik S, Cuervo AM. Autophagy as a cell-repair mechanism: activation of chaperone-mediated autophagy during oxidative stress. Mol Aspects Med. 2006;27(5-6):444-454.
35. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6(4):463-477.
36. Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc Natl Acad Sci U S A. 2004;101(10):3438-3443.
37. Lee CY, Baehrecke EH. Steroid regulation of autophagic programmed cell death during development. Development. 2001;128(8):1443-1455.
38. Rodriguez-Enriquez S, He L, Lemasters JJ. Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol. 2004;36(12):2463-2472.
39. Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol. 2002;157(3):455-468.
40. Lipinski MM, Yuan J. Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol. 2004;4(1):85-90.
41. Venkatraman P, Wetzel R, Tanaka M, Nukina N, Goldberg AL. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell. 2004;14(1):95-104.
42. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278(27):25009-25013.
43. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585-595.
44. Yuan J, Lipinski M, Degterev A. Diversity in the mechanisms of neuronal cell death. Neuron. 2003;40(2):401-413.
45. Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N. A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron. 2002;35(5):921-933.
46. Cataldo AM, Barnett JL, Pieroni C, Nixon RA. Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci. 1997;17(16):6142-6151.
47. Fortun J, Dunn WA, Jr., Joy S, Li J, Notterpek L. Emerging role for autophagy in the removal of aggresomes in Schwann cells. J Neurosci. 2003;23(33):10672-10680.
48. Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283(46):31315-31322.
49. Sha D, Chin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet. 2010;19(2):352-363.
50. Gorbacheva L, Pinelis V, Ishiwata S, Strukova S, Reiser G. Activated protein C prevents glutamate- and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons. Neuroscience. 2010;165(4):1138-1146.
51. Nijboer CH, Heijnen CJ, Groenendaal F, May MJ, van Bel F, Kavelaars A. A dual role of the NF-kappaB pathway in neonatal hypoxic-ischemic brain damage. Stroke. 2008;39(9):2578-2586.
52. Qin ZH, Tao LY, Chen X. Dual roles of NF-kappaB in cell survival and implications of NF-kappaB inhibitors in neuroprotective therapy. Acta Pharmacol Sin. 2007;28(12):1859-1872.
53. Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Kohrmann M, Potrovita I, Maegele I, Beyer C, Burke JR, Hasan MT, Bujard H, Wirth T,Pasparakis M, Schwaninger M. IKK mediates ischemia-induced neuronal death. Nat Med. 2005;11(12):1322-1329.
54. Huang CY, Fujimura M, Noshita N, Chang YY, Chan PH. SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21(2):163-173.
55. Bui NT, Livolsi A, Peyron JF, Prehn JH. Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha. J Cell Biol. 2001;152(4):753-764.
56. Zhang XD, Wang Y, Zhang X, Han R, Wu JC, Liang ZQ, Gu ZL, Han F, Fukunaga K, Qin ZH. p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum. Autophagy. 2009;5(3):339-350.
57. Kim R, Emi M, Tanabe K. Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol. 2006;57(5):545-553.
58. Lemasters JJ. Modulation of mitochondrial membrane permeability in pathogenesis, autophagy and control of metabolism. J Gastroenterol Hepatol. 2007;22 Suppl 1:S31-37.
59. Chen Y, Gibson SB. Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy. 2008;4(2):246-248.
60. Moreira PI, Santos MS, Oliveira CR. Alzheimer's disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal. 2007;9(10):1621-1630.
61. Yan CH, Yang YP, Qin ZH, Gu ZL, Reid P, Liang ZQ. Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells. Acta Pharmacol Sin. 2007;28(4):540-548.
62. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126(1):121-134.
63. Crighton D, Wilkinson S, Ryan KM. DRAM links autophagy to p53 and programmed cell death. Autophagy. 2007;3(1):72-74.
64. Dolga AM, Granic I, Blank T, Knaus HG, Spiess J, Luiten PG, Eisel UL, Nijholt IM. TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappaB-dependent up-regulation of K2.2 channels. J Neurochem. 2008;107(4):1158-1167.
65. Lebrun-Julien F, Duplan L, Pernet V, Osswald I, Sapieha P, Bourgeois P, Dickson K, Bowie D, Barker PA, Di Polo A. Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism. J Neurosci. 2009;29(17):5536-5545.
66. Qin ZH, Wang Y, Chen RW, Wang X, Ren M, Chuang DM, Chase TN. Prostaglandin A(1) protects striatal neurons against excitotoxic injury in rat striatum. J Pharmacol Exp Ther. 2001;297(1):78-87.
67. Shumway SD, Miyamoto S. A mechanistic insight into a proteasome-independent constitutive inhibitor kappaBalpha (IkappaBalpha) degradation and nuclear factor kappaB (NF-kappaB) activation pathway in WEHI-231 B-cells. Biochem J. 2004;380(Pt 1):173-180.
68. Hook VY. Unique neuronal functions of cathepsin L and cathepsin B in secretory vesicles: biosynthesis of peptides in neurotransmission and neurodegenerative disease. Biol Chem. 2006;387(10-11):1429-1439.
69. Fei XF, Qin ZH, Xiang B, Li LY, Han F, Fukunaga K, Liang ZQ. Olomoucine inhibits cathepsin L nuclear translocation, activates autophagy and attenuates toxicity of 6-hydroxydopamine. Brain Res. 2009;1264:85-97.
70. Bankstahl JP, Hoffmann K, Bethmann K, Loscher W. Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. Neuropharmacology. 2008;54(6):1006-1016.
71. Maier C, Dertwinkel R, Mansourian N, Hosbach I, Schwenkreis P, Senne I, Skipka G, Zenz M, Tegenthoff M. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain--results of a randomized double-blinded, placebo-controlled trial. Pain. 2003;103(3):277-283.
72. Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci. 1999;19(10):4023-4033.
73. Qin ZH, Wang Y, Nakai M, Chase TN. Nuclear factor-kappa B contributes to excitotoxin-induced apoptosis in rat striatum. Mol Pharmacol. 1998;53(1):33-42.
74. Wang Y, Dong XX, Cao Y, Liang ZQ, Han R, Wu JC, Gu ZL, Qin ZH. p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms. Eur J Neurosci. 2009;30(12):2258-2270.
75. Liang ZQ, Li YL, Zhao XL, Han R, Wang XX, Wang Y, Chase TN, Bennett MC, Qin ZH. NF-kappaB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. Brain Res. 2007;1145:190-203.
76. Rossi F, Cattaneo E. Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci. 2002;3(5):401-409.
77. Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol. 1999;144(5):891-901.
78. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9(6):1799-1805.
79. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19(21):5720-5728.
80. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672-676.
81. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100(25):15077-15082.
82. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, Gudkov AV. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science. 1999;285(5434):1733-1737.
83. Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, Greig NH, Mattson MP. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem. 2001;77(1):220-228.
84. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press; 1998.
85. Gal J, Strom AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, Zhu H. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem. 2009;111(4):1062-1073.
86. Yue Z. Regulation of neuronal autophagy in axon: implication of autophagy in axonal function and dysfunction/degeneration. Autophagy. 2007;3(2):139-141.
87. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181-197.
88. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282(33):24131-24145.
89. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290(5497):1717-1721.
90. Akdemir F, Farkas R, Chen P, Juhasz G, Medved'ova L, Sass M, Wang L, Wang X, Chittaranjan S, Gorski SM, Rodriguez A, Abrams JM. Autophagy occurs upstream or parallel to the apoptosome during histolytic cell death. Development. 2006;133(8):1457-1465.
91. Shacka JJ, Klocke BJ, Shibata M, Uchiyama Y, Datta G, Schmidt RE, Roth KA. Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons. Mol Pharmacol. 2006;69(4):1125-1136.
92. Yan CH, Liang ZQ, Gu ZL, Yang YP, Reid P, Qin ZH. Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon. 2006;47(5):521-530.
93. Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L, Tolkovsky A. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 2005;1(1):11-22.
94. Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN, McKinnon PJ, Cleveland JL, Zambetti GP. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell. 2003;4(4):321-328.
95. Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan P, Drummond-Main C, Poulter MO, Ferguson SS, Strasser A, Cregan SP. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci. 2007;27(47):12989-12999.
96. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303(5660):1010-1014.
97. Lahiry L, Saha B, Chakraborty J, Bhattacharyya S, Chattopadhyay S, Banerjee S, Choudhuri T, Mandal D, Bhattacharyya A, Sa G, Das T. Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis. Apoptosis. 2008;13(6):771-781.
98. Gaytan M, Morales C, Sanchez-Criado JE, Gaytan F. Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum. Cell Tissue Res. 2008;331(2):509-517.
99. Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD, Han F, Fukunaga K, Qin ZH. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy. 2008;4(6):762-769.
100. Kamada Y, Sekito T, Ohsumi Y. Autophagy in yeast: a TOR-mediated response to nutrient starvation. Curr Top Microbiol Immunol. 2004;279:73-84.
101. Komarova EA, Neznanov N, Komarov PG, Chernov MV, Wang K, Gudkov AV. p53 inhibitor pifithrin alpha can suppress heat shock and glucocorticoid signaling pathways. J Biol Chem. 2003;278(18):15465-15468.
102. Strom E, Sathe S, Komarov PG, Chernova OB, Pavlovska I, Shyshynova I, Bosykh DA, Burdelya LG, Macklis RM, Skaliter R, Komarova EA, Gudkov AV. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat Chem Biol. 2006;2(9):474-479.
103. Green DR, Chipuk JE. p53 and metabolism: Inside the TIGAR. Cell. 2006;126(1):30-32.
104. Sohn D, Graupner V, Neise D, Essmann F, Schulze-Osthoff K, Janicke RU. Pifithrin-alpha protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53. Cell Death Differ. 2009;16(6):869-878.
105. Liberski PP, Sikorska B, Bratosiewicz-Wasik J, Gajdusek DC, Brown P. Neuronal cell death in transmissible spongiform encephalopathies (prion diseases) revisited: from apoptosis to autophagy. Int J Biochem Cell Biol. 2004;36(12):2473-2490.
106. Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5(11):886-897.
107. Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y, Schulz-Schaeffer W, Watanabe T, Waguri S, Kametaka S, Shibata M, Yamamoto K, Kominami E, Peters C, von Figura K, Uchiyama Y. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci. 2000;20(18):6898-6906.
108. Kim YJ, Sapp E, Cuiffo BG, Sobin L, Yoder J, Kegel KB, Qin ZH, Detloff P, Aronin N, DiFiglia M. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis. 2006;22(2):346-356.