Abstract
Delayed neuronal death in the penumbral region of a stroke is largely responsible for many negative implications seen in stroke victims. This type of neuronal death occurs in many forms, including apoptosis, necrosis, and alternative mechanisms. Although caspases are usually associated with apoptosis, there are several morphologically and biochemically distinct types of cell death that are independent of caspase activation. Downstream effectors and processes of mitochondrial damage, such as AIF, endonuclease G, BNIP3, mitophagy, mitochondrial biogenesis, chaperone-mediated autophagy, reactive oxygen species production as well as parallel endoplasmic reticular stress and lysosomal dysfunction, have all been shown to play a role in post-stroke delayed neuronal cell death. In this chapter, we attempt to summarize these caspase-independent events and their potential therapeutic applications as targets for intervention.
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References
Boyce M, Degterev A, Yuan J. Caspases: an ancient cellular sword of Damocles. Cell Death Differ. 2004;11:29–37.
Golstein P, Aubry L, Levraud JP. Cell-death alternative model organisms: why and which? Nat Rev Mol Cell Biol. 2003;4:798–807.
Garrido C, Kroemer G. Life’s smile, death’s grin: vital functions of apoptosis-executing proteins. Curr Opin Cell Biol. 2004;16:639–46.
Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med. 2005;11:725–30.
Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4:399–415.
Lang-Rollin IC, Rideout HJ, Noticewala M, Stefanis L. Mechanisms of caspase-independent neuronal death: energy depletion and free radical generation. J Neurosci. 2003;23:11015–25.
Le DA, Wu Y, Huang Z, Matsushita K, Plesnila N, Augustinack JC, et al. Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci U S A. 2002;99:15188–93.
Didenko VV, Ngo H, Minchew CL, Boudreaux DJ, Widmayer MA, Baskin DS. Caspase-3-dependent and -independent apoptosis in focal brain ischemia. Mol Med. 2002;8:347–52.
Himi T, Ishizaki Y, Murota S. A caspase inhibitor blocks ischaemia-induced delayed neuronal death in the gerbil. Eur J Neurosci. 1998;10:777–81.
Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, et al. Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol. 2002;158:507–17.
MacManus JP, Rasquinha I, Tuor U, Preston E. Detection of higher-order 50- and 10-kbp DNA fragments before apoptotic internucleosomal cleavage after transient cerebral ischemia. J Cereb Blood Flow Metab. 1997;17:376–87.
Repici M, Mariani J, Borsello T. Neuronal death and neuroprotection: a review. Methods Mol Biol. 2007;399:1–14.
Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, et al. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci. 1995;15:1001–11.
Chen J, Nagayama T, Jin K, Stetler RA, Zhu RL, Graham SH, et al. Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci. 1998;18:4914–28.
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52.
Cho BB, Toledo-Pereyra LH. Caspase-independent programmed cell death following ischemic stroke. J Invest Surg. 2008;21:141–7.
Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol. 2000;20:5454–68.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.
Garcia JH, Liu KF, Ye ZR, Gutierrez JA. Incomplete infarct and delayed neuronal death after transient middle cerebral artery occlusion in rats. Stroke. 1997;28:2303–9; discussion 10.
Nedergaard M. Neuronal injury in the infarct border: a neuropathological study in the rat. Acta Neuropathol. 1987;73:267–74.
Sairanen T, Karjalainen-Lindsberg ML, Paetau A, Ijas P, Lindsberg PJ. Apoptosis dominant in the periinfarct area of human ischaemic stroke—a possible target of anti-apoptotic treatments. Brain. 2006;129:189–99.
Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A. 2001;98:13681–6.
Sattler R, Tymianski M. Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol. 2001;24:107–29.
Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci. 1998;1:366–73.
Syntichaki P, Xu K, Driscoll M, Tavernarakis N. Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature. 2002;419:939–44.
Yamashima T, Kohda Y, Tsuchiya K, Ueno T, Yamashita J, Yoshioka T, et al. Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on “calpain-cathepsin hypothesis”. Eur J Neurosci. 1998;10:1723–33.
Yuan J, Lipinski M, Degterev A. Diversity in the mechanisms of neuronal cell death. Neuron. 2003;40:401–13.
de Murcia G, Schreiber V, Molinete M, Saulier B, Poch O, Masson M, et al. Structure and function of poly(ADP-ribose) polymerase. Mol Cell Biochem. 1994;138:15–24.
Nixon RA. Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci. 2006;29:528–35.
Qin AP, Liu CF, Qin YY, Hong LZ, Xu M, Yang L, et al. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy. 2010;6:738–53.
Chu CT. Eaten alive: autophagy and neuronal cell death after hypoxia-ischemia. Am J Pathol. 2008;172:284–7.
Chu CT, Plowey ED, Dagda RK, Hickey RW, Cherra III SJ, Clark RS. Autophagy in neurite injury and neurodegeneration: in vitro and in vivo models. Methods Enzymol. 2009;453:217–49.
Canu N, Tufi R, Serafino AL, Amadoro G, Ciotti MT, Calissano P. Role of the autophagic-lysosomal system on low potassium-induced apoptosis in cultured cerebellar granule cells. J Neurochem. 2005;92:1228–42.
Uchiyama Y. Autophagic cell death and its execution by lysosomal cathepsins. Arch Histol Cytol. 2001;64:233–46.
Schwartz LM, Smith SW, Jones ME, Osborne BA. Do all programmed cell deaths occur via apoptosis? Proc Natl Acad Sci U S A. 1993;90:980–4.
Bursch W, Ellinger A, Gerner C, Frohwein U, Schulte-Hermann R. Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann N Y Acad Sci. 2000;926:1–12.
Bursch W, Hochegger K, Torok L, Marian B, Ellinger A, Hermann RS. Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci. 2000;113(Pt 7):1189–98.
Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol. 2008;172:454–69.
Zhu C, Wang X, Xu F, Bahr BA, Shibata M, Uchiyama Y, et al. The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ. 2005;12:162–76.
Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, et al. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol. 2006;169:566–83.
Puyal J, Clarke PG. Targeting autophagy to prevent neonatal stroke damage. Autophagy. 2009;5:1060–1.
Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304:1500–2.
Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol. 2006;8:1124–32.
Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 2005;1:11–22.
Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, et al. Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A. 2006;103:4952–7.
Kirino T, Tamura A, Sano K. A reversible type of neuronal injury following ischemia in the gerbil hippocampus. Stroke. 1986;17:455–9.
Lo EH. A new penumbra: transitioning from injury into repair after stroke. Nat Med. 2008;14:497–500.
Horbinski C, Chu CT. Kinase signaling cascades in the mitochondrion: a matter of life or death. Free Radic Biol Med. 2005;38:2–11.
Galluzzi L, Zamzami N, de la Motte Rouge T, Lemaire C, Brenner C, Kroemer G. Methods for the assessment of mitochondrial membrane permeabilization in apoptosis. Apoptosis. 2007;12:803–13.
Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000;6:513–9.
Galluzzi L, Morselli E, Kepp O, Kroemer G. Targeting post-mitochondrial effectors of apoptosis for neuroprotection. Biochim Biophys Acta. 2009;1787:402–13.
Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–9.
Vosler PS, Graham SH, Wechsler LR, Chen J. Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics. Stroke. 2009;40:3149–55.
Krantic S, Mechawar N, Reix S, Quirion R. Apoptosis-inducing factor: a matter of neuron life and death. Prog Neurobiol. 2007;81:179–96.
Zhu C, Wang X, Deinum J, Huang Z, Gao J, Modjtahedi N, et al. Cyclophilin A participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia. J Exp Med. 2007;204:1741–8.
Cande C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C, et al. AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene. 2004;23:1514–21.
Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ. 1999;6:516–24.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397:441–6.
Penninger JM, Kroemer G. Mitochondria, AIF and caspases—rivaling for cell death execution. Nat Cell Biol. 2003;5:97–9.
Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab. 2004;24:458–66.
Hisatomi T, Sakamoto T, Murata T, Yamanaka I, Oshima Y, Hata Y, et al. Relocalization of apoptosis-inducing factor in photoreceptor apoptosis induced by retinal detachment in vivo. Am J Pathol. 2001;158:1271–8.
Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 2000;14:729–39.
Cao G, Clark RS, Pei W, Yin W, Zhang F, Sun FY, et al. Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab. 2003;23:1137–50.
Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, et al. Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci. 2005;25:10262–72.
Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, et al. Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem. 2003;86:306–17.
Zhu C, Wang X, Huang Z, Qiu L, Xu F, Vahsen N, et al. Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. Cell Death Differ. 2007;14:775–84.
Tsujimoto Y. Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol. 2003;195:158–67.
van Loo G, Saelens X, Matthijssens F, Schotte P, Beyaert R, Declercq W, et al. Caspases are not localized in mitochondria during life or death. Cell Death Differ. 2002;9:1207–11.
Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999;341(Pt 2):233–49.
Donovan M, Cotter TG. Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death. Biochim Biophys Acta. 2004;1644:133–47.
Cande C, Cecconi F, Dessen P, Kroemer G. Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? J Cell Sci. 2002;115:4727–34.
Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;412:95–9.
van Loo G, Schotte P, van Gurp M, Demol H, Hoorelbeke B, Gevaert K, et al. Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation. Cell Death Differ. 2001;8:1136–42.
Zhang J, Dong M, Li L, Fan Y, Pathre P, Dong J, et al. Endonuclease G is required for early embryogenesis and normal apoptosis in mice. Proc Natl Acad Sci U S A. 2003;100:15782–7.
Lee BI, Lee DJ, Cho KJ, Kim GW. Early nuclear translocation of endonuclease G and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Neurosci Lett. 2005;386:23–7.
Tanaka S, Takehashi M, Iida S, Kitajima T, Kamanaka Y, Stedeford T, et al. Mitochondrial impairment induced by poly(ADP-ribose) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation. J Neurochem. 2005;95:179–90.
Zhang Z, Yang X, Zhang S, Ma X, Kong J. BNIP3 upregulation and EndoG translocation in delayed neuronal death in stroke and in hypoxia. Stroke. 2007;38:1606–13.
Vande Walle L, Van Damme P, Lamkanfi M, Saelens X, Vandekerckhove J, Gevaert K, et al. Proteome-wide identification of HtrA2/Omi Substrates. J Proteome Res. 2007;6:1006–15.
Saito A, Hayashi T, Okuno S, Nishi T, Chan PH. Modulation of the Omi/HtrA2 signalling pathway after transient focal cerebral ischemia in mouse brains that overexpress SOD1. Brain Res Mol Brain Res. 2004;127:89–95.
Siegelin MD, Kossatz LS, Winckler J, Rami A. Regulation of XIAP and Smac/DIABLO in the rat hippocampus following transient forebrain ischemia. Neurochem Int. 2005;46:41–51.
Saito A, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH. Interaction between XIAP and Smac/DIABLO in the mouse brain after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2003;23:1010–9.
Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J, Fukuuchi Y. Subcellular localization of a promoter and an inhibitor of apoptosis (Smac/DIABLO and XIAP) during brain ischemia/reperfusion. Neuroreport. 2002;13:1985–8.
Saito A, Hayashi T, Okuno S, Nishi T, Chan PH. Oxidative stress is associated with XIAP and Smac/DIABLO signaling pathways in mouse brains after transient focal cerebral ischemia. Stroke. 2004;35:1443–8.
Boyd JM. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell. 1994;79:1121.
Chen G, Cizeau J, Vande Velde C, Park JH, Bozek G, Bolton J, et al. Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins. J Biol Chem. 1999;274:7–10.
Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, et al. The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. J Exp Med. 1997;186:1975–83.
Cizeau J, Ray R, Chen G, Gietz RD, Greenberg AH. The C. elegans orthologue ceBNIP3 interacts with CED-9 and CED-3 but kills through a BH3- and caspase-independent mechanism. Oncogene. 2000;19:5453–63.
Yasuda M, D’Sa-Eipper C, Gong XL, Chinnadurai G. Regulation of apoptosis by a Caenorhabditis elegans BNIP3 homolog. Oncogene. 1998;17:2525–30.
Zhang S, Zhang Z, Sandhu G, Ma X, Yang X, Geiger JD, et al. Evidence of oxidative stress-induced BNIP3 expression in amyloid beta neurotoxicity. Brain Res. 2007;1138:221–30.
Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, et al. BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem. 2000;275:1439–48.
Bruick RK. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci U S A. 2000;97:9082–7.
Guo K, Searfoss G, Krolikowski D, Pagnoni M, Franks C, Clark K, et al. Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Cell Death Differ. 2001;8:367–76.
Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 2001;61:6669–73.
Helton R, Cui J, Scheel JR, Ellison JA, Ames C, Gibson C, et al. Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J Neurosci. 2005;25:4099–107.
Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo M, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 2004;23:2861–74.
Diaz F, Moraes CT. Mitochondrial biogenesis and turnover. Cell Calcium. 2008;44:24–35.
Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.
Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462:245–53.
Tolkovsky AM, Xue L, Fletcher GC, Borutaite V. Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease? Biochimie. 2002;84:233–40.
Nowikovsky K, Reipert S, Devenish RJ, Schweyen RJ. Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy. Cell Death Differ. 2007;14:1647–56.
Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A. 2007;104:19500–5.
Kundu M, Lindsten T, Yang CY, Wu J, Zhao F, Zhang J, et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood. 2008;112:1493–502.
Schwarten M, Mohrluder J, Ma P, Stoldt M, Thielmann Y, Stangler T, et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy. 2009;5:690–8.
Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010;11:45–51.
Elmore SP, Qian T, Grissom SF, Lemasters JJ. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 2001;15:2286–7.
Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433–46.
Jahani-Asl A, Cheung EC, Neuspiel M, MacLaurin JG, Fortin A, Park DS, et al. Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death. J Biol Chem. 2007;282:23788–98.
Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J. Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke. 2008;39:3057–63.
Dice JF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci. 1990;15:305–9.
Chiang HL, Terlecky SR, Plant CP, Dice JF. A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science. 1989;246:382–5.
Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science. 1996;273:501–3.
Agarraberes FA, Terlecky SR, Dice JF. An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol. 1997;137:825–34.
Cuervo AM, Knecht E, Terlecky SR, Dice JF. Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am J Physiol. 1995;269:C1200–8.
Wing SS, Chiang HL, Goldberg AL, Dice JF. Proteins containing peptide sequences related to Lys-Phe-Glu-Arg-Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J. 1991;275(Pt 1):165–9.
Kiffin R, Christian C, Knecht E, Cuervo AM. Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell. 2004;15:4829–40.
Cuervo AM, Hildebrand H, Bomhard EM, Dice JF. Direct lysosomal uptake of alpha 2-microglobulin contributes to chemically induced nephropathy. Kidney Int. 1999;55:529–45.
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305:1292–5.
Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, et al. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest. 2008;118:777–88.
Cuervo AM, Dice JF, Knecht E. A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins. J Biol Chem. 1997;272:5606–15.
Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, et al. Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol. 2001;3:839–43.
Ruchalski K, Mao H, Li Z, Wang Z, Gillers S, Wang Y, et al. Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem. 2006; 281: 7873–80.
Lee SH, Kwon HM, Kim YJ, Lee KM, Kim M, Yoon BW. Effects of hsp70.1 gene knockout on the mitochondrial apoptotic pathway after focal cerebral ischemia. Stroke. 2004;35:2195–9.
Matsumori Y, Hong SM, Aoyama K, Fan Y, Kayama T, Sheldon RA, et al. Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab. 2005;25:899–910.
Berridge MJ. The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium. 2002;32:235–49.
Bernales S, Papa FR, Walter P. Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol. 2006;22:487–508.
Momoi T. Conformational diseases and ER stress-mediated cell death: apoptotic cell death and autophagic cell death. Curr Mol Med. 2006;6:111–8.
Hoyer-Hansen M, Jaattela M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 2007;14:1576–82.
Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–32.
Bertolotti A, Ron D. Alterations in an IRE1-RNA complex in the mammalian unfolded protein response. J Cell Sci. 2001;114:3207–12.
Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell. 2007;25:193–205.
Demarchi F, Bertoli C, Copetti T, Tanida I, Brancolini C, Eskelinen EL, et al. Calpain is required for macroautophagy in mammalian cells. J Cell Biol. 2006;175:595–605.
Ray SK, Fidan M, Nowak MW, Wilford GG, Hogan EL, Banik NL. Oxidative stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells. Brain Res. 2000;852:326–34.
Schoonbroodt S, Ferreira V, Best-Belpomme M, Boelaert JR, Legrand-Poels S, Korner M, et al. Crucial role of the amino-terminal tyrosine residue 42 and the carboxyl-terminal PEST domain of I kappa B alpha in NF-kappa B activation by an oxidative stress. J Immunol. 2000;164:4292–300.
Yamashima T, Tonchev AB, Tsukada T, Saido TC, Imajoh-Ohmi S, Momoi T, et al. Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates. Hippocampus. 2003;13:791–800.
Yamashima T, Saido TC, Takita M, Miyazawa A, Yamano J, Miyakawa A, et al. Transient brain ischaemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys. Eur J Neurosci. 1996;8:1932–44.
Ray SK, Wilford GG, Crosby CV, Hogan EL, Banik NL. Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells. Brain Res. 1999;829:18–27.
Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature. 2000;405:360–4.
Mouatt-Prigent A, Karlsson JO, Agid Y, Hirsch EC. Increased M-calpain expression in the mesencephalon of patients with Parkinson’s disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? Neuroscience. 1996;73:979–87.
Yamashima T. Ca2+-dependent proteases in ischemic neuronal death: a conserved “calpain-cathepsin cascade” from nematodes to primates. Cell Calcium. 2004;36:285–93.
Adamec E, Mohan PS, Cataldo AM, Vonsattel JP, Nixon RA. Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer’s disease. Neuroscience. 2000;100:663–75.
Yamashima T. Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol. 2000;62:273–95.
Chan PH. Role of oxidants in ischemic brain damage. Stroke. 1996;27:1124–9.
Takano J, Tomioka M, Tsubuki S, Higuchi M, Iwata N, Itohara S, et al. Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice. J Biol Chem. 2005;280:16175–84.
Muntener K, Zwicky R, Csucs G, Rohrer J, Baici A. Exon skipping of cathepsin B: mitochondrial targeting of a lysosomal peptidase provokes cell death. J Biol Chem. 2004;279:41012–7.
Guicciardi ME, Miyoshi H, Bronk SF, Gores GJ. Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications. Am J Pathol. 2001;159:2045–54.
Canbay A, Guicciardi ME, Higuchi H, Feldstein A, Bronk SF, Rydzewski R, et al. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest. 2003;112:152–9.
Benchoua A, Braudeau J, Reis A, Couriaud C, Onteniente B. Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia. J Cereb Blood Flow Metab. 2004;24:1272–9.
Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.
Leber B, Lin J, Andrews DW. Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis. 2007;12:897–911.
Reed JC. Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ. 2006;13:1378–86.
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59.
Lalier L, Cartron PF, Juin P, Nedelkina S, Manon S, Bechinger B, et al. Bax activation and mitochondrial insertion during apoptosis. Apoptosis. 2007;12:887–96.
Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L, et al. Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death. Oncogene. 2008;27:4221–32.
Zamzami N, El Hamel C, Maisse C, Brenner C, Munoz-Pinedo C, Belzacq AS, et al. Bid acts on the permeability transition pore complex to induce apoptosis. Oncogene. 2000;19:6342–50.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell. 2005;17:525–35.
Kim R. Unknotting the roles of Bcl-2 and Bcl-xL in cell death. Biochem Biophys Res Commun. 2005;333:336–43.
Pinton P, Rizzuto R. Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ. 2006;13:1409–18.
Zamzami N, Larochette N, Kroemer G. Mitochondrial permeability transition in apoptosis and necrosis. Cell Death Differ. 2005;12 Suppl 2:1478–80.
Zoratti M, Szabo I, De Marchi U. Mitochondrial permeability transitions: how many doors to the house? Biochim Biophys Acta. 2005;1706:40–52.
Brenner C, Cadiou H, Vieira HL, Zamzami N, Marzo I, Xie Z, et al. Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene. 2000;19:329–36.
Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 anti-apoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122:927–39.
Rodriguez D, Rojas-Rivera D, Hetz C. Integrating stress signals at the endoplasmic reticulum: the BCL-2 protein family rheostat. Biochim Biophys Acta. 2011;1813:564–74.
Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, et al. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 2007;14:230–9.
Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26:9220–31.
Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem. 2006;281:30299–304.
Ding WX, Ni HM, Gao W, Hou YF, Melan MA, Chen X, et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem. 2007;282:4702–10.
Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65.
Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112:1809–20.
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;100:15077–82.
Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 2007;26:2527–39.
Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy. 2007;3:374–6.
Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29:2570–81.
Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, et al. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy. 2008;4:195–204.
Chinnadurai G, Vijayalingam S, Gibson SB. BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene. 2008;27 Suppl 1:S114–27.
Gillardon F, Kiprianova I, Sandkuhler J, Hossmann KA, Spranger M. Inhibition of caspases prevents cell death of hippocampal CA1 neurons, but not impairment of hippocampal long-term potentiation following global ischemia. Neuroscience. 1999;93:1219–22.
Strosznajder R, Gajkowska B. Effect of 3-aminobenzamide on Bcl-2, Bax and AIF localization in hippocampal neurons altered by ischemia-reperfusion injury. the immunocytochemical study. Acta Neurobiol Exp (Wars). 2006;66:15–22.
Niimura M, Takagi N, Takagi K, Mizutani R, Ishihara N, Matsumoto K, et al. Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia. J Cereb Blood Flow Metab. 2006;26:1354–65.
Li X, Nemoto M, Xu Z, Yu SW, Shimoji M, Andrabi SA, et al. Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus. Neuroscience. 2007;144:56–65.
Sun Y, Ouyang YB, Xu L, Chow AM, Anderson R, Hecker JG, et al. The carboxyl-terminal domain of inducible Hsp70 protects from ischemic injury in vivo and in vitro. J Cereb Blood Flow Metab. 2006;26:937–50.
Parrish J, Li L, Klotz K, Ledwich D, Wang X, Xue D. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature. 2001;412:90–4.
Kalinowska M, Garncarz W, Pietrowska M, Garrard WT, Widlak P. Regulation of the human apoptotic DNase/RNase endonuclease G: involvement of Hsp70 and ATP. Apoptosis. 2005;10:821–30.
Rustin P. The use of antioxidants in Friedreich’s ataxia treatment. Expert Opin Investig Drugs. 2003;12:569–75.
Elibol B, Soylemezoglu F, Unal I, Fujii M, Hirt L, Huang PL, et al. Nitric oxide is involved in ischemia-induced apoptosis in brain: a study in neuronal nitric oxide synthase null mice. Neuroscience. 2001;105:79–86.
Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, et al. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem. 2001;77:220–8.
Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA. Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci. 1996;16:1337–45.
Gao Y, Signore AP, Yin W, Cao G, Yin XM, Sun F, et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J Cereb Blood Flow Metab. 2005;25:694–712.
Guan QH, Pei DS, Zong YY, Xu TL, Zhang GY. Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase (JNK) via nuclear and non-nuclear pathways. Neuroscience. 2006;139:609–27.
Mattson MP, Kroemer G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med. 2003;9:196–205.
Stavrovskaya IG, Narayanan MV, Zhang W, Krasnikov BF, Heemskerk J, Young SS, et al. Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology. J Exp Med. 2004;200:211–22.
Hetz C, Vitte PA, Bombrun A, Rostovtseva TK, Montessuit S, Hiver A, et al. Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia. J Biol Chem. 2005;280:42960–70.
Rodrigues CM, Sola S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry. 2003;42:3070–80.
Rodrigues CM, Spellman SR, Sola S, Grande AW, Linehan-Stieers C, Low WC, et al. Neuroprotection by a bile acid in an acute stroke model in the rat. J Cereb Blood Flow Metab. 2002;22:463–71.
Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, et al. Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A. 2003;100:6087–92.
Saavedra RA, Murray M, de Lacalle S, Tessler A. In vivo neuroprotection of injured CNS neurons by a single injection of a DNA plasmid encoding the Bcl-2 gene. Prog Brain Res. 2000;128:365–72.
Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, et al. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron. 1994;13:1017–30.
Zhao H, Yenari MA, Cheng D, Sapolsky RM, Steinberg GK. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem. 2003;85:1026–36.
Wiessner C, Allegrini PR, Rupalla K, Sauer D, Oltersdorf T, McGregor AL, et al. Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci Lett. 1999;268:119–22.
Culmsee C, Plesnila N. Targeting Bid to prevent programmed cell death in neurons. Biochem Soc Trans. 2006;34:1334–40.
Plesnila N, Zinkel S, Le DA, Amin-Hanjani S, Wu Y, Qiu J, et al. BID mediates neuronal cell death after oxygen/glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci U S A. 2001;98:15318–23.
Plesnila N, Zinkel S, Amin-Hanjani S, Qiu J, Korsmeyer SJ, Moskowitz MA. Function of BID—a molecule of the bcl-2 family—in ischemic cell death in the brain. Eur Surg Res. 2002;34:37–41.
Tehranian R, Rose ME, Vagni V, Pickrell AM, Griffith RP, Liu H, et al. Disruption of Bax protein prevents neuronal cell death but produces cognitive impairment in mice following traumatic brain injury. J Neurotrauma. 2008;25:755–67.
Gibson ME, Han BH, Choi J, Knudson CM, Korsmeyer SJ, Parsadanian M, et al. BAX contributes to apoptotic-like death following neonatal hypoxia-ischemia: evidence for distinct apoptosis pathways. Mol Med. 2001;7:644–55.
Fischer SF, Vier J, Kirschnek S, Klos A, Hess S, Ying S, et al. Chlamydia inhibit host cell apoptosis by degradation of proapoptotic BH3-only proteins. J Exp Med. 2004;200:905–16.
Rami A, Langhagen A, Steiger S. Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis. 2008;29:132–41.
Puyal J, Vaslin A, Mottier V, Clarke PG. Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann Neurol. 2009;66:378–89.
Asoh S, Ohsawa I, Mori T, Katsura K, Hiraide T, Katayama Y, et al. Protection against ischemic brain injury by protein therapeutics. Proc Natl Acad Sci U S A. 2002;99:17107–12.
Hayashi K, Morishita R, Nakagami H, Yoshimura S, Hara A, Matsumoto K, et al. Gene therapy for preventing neuronal death using hepatocyte growth factor: in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons. Gene Ther. 2001;8:1167–73.
Nuglisch J, Karkoutly C, Mennel HD, Rossberg C, Krieglstein J. Protective effect of nimodipine against ischemic neuronal damage in rat hippocampus without changing postischemic cerebral blood flow. J Cereb Blood Flow Metab. 1990;10:654–9.
Mossakowski MJ, Gadamski R. Nimodipine prevents delayed neuronal death of sector CA1 pyramidal cells in short-term forebrain ischemia in Mongolian gerbils. Stroke. 1990;21:IV120–2.
Hadley MN, Zabramski JM, Spetzler RF, Rigamonti D, Fifield MS, Johnson PC. The efficacy of intravenous nimodipine in the treatment of focal cerebral ischemia in a primate model. Neurosurgery. 1989;25:63–70.
Nag D, Garg RK, Varma M. A randomized double-blind controlled study of nimodipine in acute cerebral ischemic stroke. Indian J Physiol Pharmacol. 1998;42:555–8.
Kakarieka A, Schakel EH, Fritze J. Clinical experiences with nimodipine in cerebral ischemia. J Neural Transm Suppl. 1994;43:13–21.
Mattson MP, Zhu H, Yu J, Kindy MS. Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis. J Neurosci. 2000;20:1358–64.
Wei H, Perry DC. Dantrolene is cytoprotective in two models of neuronal cell death. J Neurochem. 1996;67:2390–8.
Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265:1883–5.
Satoh K, Ikeda Y, Shioda S, Tobe T, Yoshikawa T. Edarabone scavenges nitric oxide. Redox Rep. 2002;7:219–22.
Kamii H, Mikawa S, Murakami K, Kinouchi H, Yoshimoto T, Reola L, et al. Effects of nitric oxide synthase inhibition on brain infarction in SOD-1-transgenic mice following transient focal cerebral ischemia. J Cereb Blood Flow Metab. 1996;16:1153–7.
Hara H, Nagasawa H, Kogure K. Nimodipine prevents postischemic brain damage in the early phase of focal cerebral ischemia. Stroke. 1990;21:IV102–4.
Wolz P, Krieglstein J. Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacology. 1996;35:369–75.
Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res. 1998;53:613–25.
Gray J, Haran MM, Schneider K, Vesce S, Ray AM, Owen D, et al. Evidence that inhibition of cathepsin-B contributes to the neuroprotective properties of caspase inhibitor Tyr-Val-Ala-Asp-chloromethyl ketone. J Biol Chem. 2001;276:32750–5.
Endres M, Fink K, Zhu J, Stagliano NE, Bondada V, Geddes JW, et al. Neuroprotective effects of gelsolin during murine stroke. J Clin Invest. 1999;103:347–54.
Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920–6.
Acknowledgments
This work was supported by grants from the Canadian Institutes of Health Research, Canadian Stroke Network and Manitoba Health Research Council (to J. Kong). Dr. Jiming Kong received a salary award from the Heart and Stroke Foundation of Canada. Ms. Ruoyang Shi received a Manitoba Health Research Council/Manitoba Institute of Child Health Graduate Studentship.
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Shi, R., Weng, J., Szelemej, P., Kong, J. (2012). Caspase-Independent Stroke Targets. In: Lapchak, P., Zhang, J. (eds) Translational Stroke Research. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9530-8_7
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