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Article: Lysosomal membrane permeabilization is involved in oxidative stress-induced apoptotic cell death in LAMP2-deficient iPSCs-derived cerebral cortical neurons

TitleLysosomal membrane permeabilization is involved in oxidative stress-induced apoptotic cell death in LAMP2-deficient iPSCs-derived cerebral cortical neurons
Authors
KeywordsLAMP2 deficiency
iPSCs-derived cerebral cortical neurons
Lysosomal membrane permeabilization
Oxidative stress-induced apoptosis
Issue Date2016
PublisherElsevier BV. The Journal's web site is located at http://www.journals.elsevier.com/biochemistry-and-biophysics-reports/
Citation
Biochemistry and Biophysics Reports, 2016, v. 5, p. 335-345 How to Cite?
AbstractPatients with Danon disease may suffer from severe cardiomyopathy, skeletal muscle dysfunction as well as varying degrees of mental retardation, in which the primary deficiency of lysosomal membrane-associated protein-2 (LAMP2) is considerably associated. Owing to the scarcity of human neurons, the pathological role of LAMP2 deficiency in neural injury of humans remains largely elusive. However, the application of induced pluripotent stem cells (iPSCs) may shed light on overcoming such scarcity. In this study, we obtained iPSCs derived from a patient carrying a mutated LAMP2 gene that is associated with Danon disease. By differentiating such LAMP2-deficient iPSCs into cerebral cortical neurons and with the aid of various biochemical assays, we demonstrated that the LAMP2-deficient neurons are more susceptible to mild oxidative stress-induced injury. The data from MTT assay and apoptotic analysis demonstrated that there was no notable difference in cellular viability between the normal and LAMP2-deficient neurons under non-stressed condition. When exposed to mild oxidative stress (10 μM H2O2), the LAMP2-deficient neurons exhibited a significant increase in apoptosis. Surprisingly, we did not observe any aberrant accumulation of autophagic materials in the LAMP2-deficient neurons under such stress condition. Our results from cellular fractionation and inhibitor blockade experiments further revealed that oxidative stress-induced apoptosis in the LAMP2-deficient cortical neurons was caused by increased abundance of cytosolic cathepsin L. These results suggest the involvement of lysosomal membrane permeabilization in the LAMP2 deficiency associated neural injury.
Persistent Identifierhttp://hdl.handle.net/10722/232015
ISSN
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorLaw, CY-
dc.contributor.authorSiu, CW-
dc.contributor.authorFan, K-
dc.contributor.authorLai, WH-
dc.contributor.authorAu, KW-
dc.contributor.authorLau, YM-
dc.contributor.authorWong, LY-
dc.contributor.authorHo, JCY-
dc.contributor.authorLee, YK-
dc.contributor.authorTse, HF-
dc.contributor.authorNg, KM-
dc.date.accessioned2016-09-20T05:27:00Z-
dc.date.available2016-09-20T05:27:00Z-
dc.date.issued2016-
dc.identifier.citationBiochemistry and Biophysics Reports, 2016, v. 5, p. 335-345-
dc.identifier.issn2405-5808-
dc.identifier.urihttp://hdl.handle.net/10722/232015-
dc.description.abstractPatients with Danon disease may suffer from severe cardiomyopathy, skeletal muscle dysfunction as well as varying degrees of mental retardation, in which the primary deficiency of lysosomal membrane-associated protein-2 (LAMP2) is considerably associated. Owing to the scarcity of human neurons, the pathological role of LAMP2 deficiency in neural injury of humans remains largely elusive. However, the application of induced pluripotent stem cells (iPSCs) may shed light on overcoming such scarcity. In this study, we obtained iPSCs derived from a patient carrying a mutated LAMP2 gene that is associated with Danon disease. By differentiating such LAMP2-deficient iPSCs into cerebral cortical neurons and with the aid of various biochemical assays, we demonstrated that the LAMP2-deficient neurons are more susceptible to mild oxidative stress-induced injury. The data from MTT assay and apoptotic analysis demonstrated that there was no notable difference in cellular viability between the normal and LAMP2-deficient neurons under non-stressed condition. When exposed to mild oxidative stress (10 μM H2O2), the LAMP2-deficient neurons exhibited a significant increase in apoptosis. Surprisingly, we did not observe any aberrant accumulation of autophagic materials in the LAMP2-deficient neurons under such stress condition. Our results from cellular fractionation and inhibitor blockade experiments further revealed that oxidative stress-induced apoptosis in the LAMP2-deficient cortical neurons was caused by increased abundance of cytosolic cathepsin L. These results suggest the involvement of lysosomal membrane permeabilization in the LAMP2 deficiency associated neural injury.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.journals.elsevier.com/biochemistry-and-biophysics-reports/-
dc.relation.ispartofBiochemistry and Biophysics Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectLAMP2 deficiency-
dc.subjectiPSCs-derived cerebral cortical neurons-
dc.subjectLysosomal membrane permeabilization-
dc.subjectOxidative stress-induced apoptosis-
dc.titleLysosomal membrane permeabilization is involved in oxidative stress-induced apoptotic cell death in LAMP2-deficient iPSCs-derived cerebral cortical neurons-
dc.typeArticle-
dc.identifier.emailSiu, CW: cwdsiu@hkucc.hku.hk-
dc.identifier.emailLai, WH: kwhlai@hku.hk-
dc.identifier.emailAu, KW: aukawing@hku.hk-
dc.identifier.emailLau, YM: vymlau@hku.hk-
dc.identifier.emailWong, LY: navywong@hkucc.hku.hk-
dc.identifier.emailHo, JCY: jennyho@hku.hk-
dc.identifier.emailLee, YK: carol801@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.emailNg, KM: skykmng@hkucc.hku.hk-
dc.identifier.authoritySiu, CW=rp00534-
dc.identifier.authorityLee, YK=rp02636-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.authorityNg, KM=rp01670-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.bbrep.2016.01.010-
dc.identifier.pmid28955840-
dc.identifier.pmcidPMC5600451-
dc.identifier.scopuseid_2-s2.0-84955462395-
dc.identifier.hkuros263821-
dc.identifier.volume5-
dc.identifier.spage335-
dc.identifier.epage345-
dc.publisher.placeNetherlands-

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