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dc.contributor.author오기욱-
dc.date.accessioned2019-03-14T08:14:51Z-
dc.date.available2019-03-14T08:14:51Z-
dc.date.issued2016-11-
dc.identifier.citationONCOTARGET, v. 7, NO 46, Page. 74496-74509en_US
dc.identifier.issn1949-2553-
dc.identifier.urihttp://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=12812&path[]=40592-
dc.identifier.urihttps://repository.hanyang.ac.kr/handle/20.500.11754/100806-
dc.description.abstractKrabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective beta-galactosylceramidase (GALC), a lysosomal enzyme responsible for cleavage of several key substrates including psychosine. Accumulation of psychosine to the cytotoxic levels in KD patients is thought to cause dysfunctions in myelinating glial cells based on a comprehensive study of demyelination in KD. However, recent evidence suggests myelin-independent neuronal death in the murine model of KD, thus indicating defective GALC in neurons as an autonomous mechanism for neuronal cell death in KD. These observations prompted us to generate induced neurons (iNeurons) from two adult-onset KD patients carrying compound heterozygous mutations (p.[K563*];[L634S]) and (p.[N228_S232delinsTP];[G286D]) to determine the direct contribution of autonomous neuronal toxicity to KD. Here we report that directly converted KD iNeurons showed not only diminished GALC activity and increased psychosine levels, as expected, but also neurite fragmentation and abnormal neuritic branching. The lysosomal-associated membrane proteins 1 (LAMP1) was expressed at higher levels than controls, LAMP1-positive vesicles were significantly enlarged and fragmented, and mitochondrial morphology and its function were altered in KD iNeurons. Strikingly, we demonstrated that psychosine was sufficient to induce neurite defects, mitochondrial fragmentation, and lysosomal alterations in iNeurons derived in healthy individuals, thus establishing the causal effect of the cytotoxic GALC substrate in KD and the autonomous neuronal toxicity in KD pathology.en_US
dc.description.sponsorshipThis work is supported in part by grants from the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (HI12C0135), the US National Human Genome Research Institute grant (HG004659) to X-D.F, and the National Research Foundation of Korea (NRF) grants funded by the Korean government, MSIP (NRF-2014R1A2A2A01004240).en_US
dc.language.isoko_KRen_US
dc.publisherIMPACT JOURNALS LLCen_US
dc.subjectkrabbe diseaseen_US
dc.subjectgloboid cell leukodystrophyen_US
dc.subjectbeta-galactosylceramidaseen_US
dc.subjectpsychosineen_US
dc.subjectinduced neuronen_US
dc.subjectGerotargeten_US
dc.titlePatient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe diseaseen_US
dc.typeArticleen_US
dc.relation.no46-
dc.relation.volume7-
dc.identifier.doi10.18632/oncotarget.12812-
dc.relation.page74496-74509-
dc.relation.journalONCOTARGET-
dc.contributor.googleauthorLim, Su Min-
dc.contributor.googleauthorChoi, Byung-Ok-
dc.contributor.googleauthorOh, Seong-Il-
dc.contributor.googleauthorChoi, Won Jun-
dc.contributor.googleauthorOh, Ki-Wook-
dc.contributor.googleauthorNahm, Minyeop-
dc.contributor.googleauthorXue, Yuanchao-
dc.contributor.googleauthorChoi, Jae Hyeok-
dc.contributor.googleauthorChoi, Ji Young-
dc.contributor.googleauthorKim, Young-Eun-
dc.relation.code2016010107-
dc.sector.campusS-
dc.sector.daehakCOLLEGE OF MEDICINE[S]-
dc.sector.departmentDEPARTMENT OF MEDICINE-
dc.identifier.pidkiwook-oh-
dc.identifier.researcherIDE-6996-2017-
dc.identifier.orcidhttp://orcid.org/0000-0001-6011-629X-


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