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The Journal of Neuroscience, March 19, 2008, 28(12):3114-3122; doi:10.1523/JNEUROSCI.0199-08.2008

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Neurobiology of Disease
Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H₂O₂ in Cultured Hippocampal Neurons

Jung Jin Hwang,^3 * Sook-Jeong Lee,^1 * Tae-Youn Kim,³ Jae-Hyung Cho,¹ and Jae-Young Koh^1,2,3

¹Neural Injury Research Laboratory, ²Department of Neurology, ³Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 138-736, Korea

Correspondence should be addressed to Jae-Young Koh, Department of Neurology, University of Ulsan College of Medicine, 388-1 Poongnap-Dong Songpa-Gu, Seoul 138-736, Korea. Email: jkko{at}amc.seoul.kr

Lysosomal membrane permeabilization (LMP) is implicated in cancer cell death. However, its role and mechanism of action in neuronal death remain to be established. In the present study, we investigate the function of cellular zinc in oxidative stress-induced LMP using hippocampal neurons. Live-cell confocal microscopy with FluoZin-3 fluorescence showed that H₂O₂ exposure induced vesicles containing labile zinc in hippocampal neurons. Double staining with LysoTracker or MitoTracker disclosed that the majority of the zinc-containing vesicles were lysosomes and not mitochondria. H₂O₂ additionally augmented the 4-hydroxy-2-nonenal (HNE) adduct level in lysosomes. Intracellular zinc chelation with TPEN [tetrakis(2-pyridylmethyl)ethylenediamine] completely blocked both HNE accumulation and neuronal death. Interestingly, within 1 h after the onset of H₂O₂ exposure, some of zinc-loaded vesicles lost their zinc signals. Consistent with the characteristics of LMP, a lysosomal enzyme, cathepsin D, was released into the cytosol, and cathepsin inhibitors partially rescued neuronal death. We further examined the possibility that HNE or zinc mediates H₂O₂-triggered LMP. Similar to H₂O₂, exposure to HNE or zinc triggered lysosomal zinc accumulation and LMP. Moreover, isolated lysosomes underwent LMP when exposed to HNE or zinc, but not H₂O₂, supporting the direct mediation of LMP by HNE and/or zinc. The appearance of zinc-containing vesicles and the increases in levels of cathepsin D and HNE, were also observed in hippocampal neurons of rats after kainate seizures. Thus, under oxidative stress, neuronal lysosomes accumulate zinc and HNE, and eventually undergo LMP, which may constitute a key mechanism of oxidative neuronal death.

Key words: lysosome; oxidative stress; cathepsin; Alzheimer's disease; neurotoxicity; kainic acid; seizure

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Received Oct. 16, 2007; revised Feb. 4, 2008; accepted Feb. 6, 2008.

Correspondence should be addressed to Jae-Young Koh, Department of Neurology, University of Ulsan College of Medicine, 388-1 Poongnap-Dong Songpa-Gu, Seoul 138-736, Korea. Email: jkko{at}amc.seoul.kr

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