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dc.contributor.author노민영-
dc.date.accessioned2017-11-02T02:21:40Z-
dc.date.available2017-11-02T02:21:40Z-
dc.date.issued2016-01-
dc.identifier.citationMOLECULAR NEURODEGENERATION, v. 11, Article number 8, Page. 1-11en_US
dc.identifier.issn1750-1326-
dc.identifier.urihttps://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-016-0075-6-
dc.identifier.urihttp://hdl.handle.net/20.500.11754/30425-
dc.description.abstractBackground: Mutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients' fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures. Results: Here, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts. Conclusions: Thus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS.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), supported in part by the US National Human Genome Research Institute grant (HG004659) to X-D.F, and supported in part by grants from the KOBIC Research Support Program to JL.en_US
dc.language.isoenen_US
dc.publisherBIOMED CENTRAL LTDen_US
dc.subjectAmyotrophic lateral sclerosisen_US
dc.subjectFused in sarcomaen_US
dc.subjectHuman cell modelsen_US
dc.subjectInduced neuronen_US
dc.subjectNuclear localization signalen_US
dc.subjectStress granulesen_US
dc.subjectNeuronal cytoplasmic inclusionen_US
dc.titleDirectly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosisen_US
dc.typeArticleen_US
dc.relation.volume11-
dc.identifier.doi10.1186/s13024-016-0075-6-
dc.relation.page1-11-
dc.relation.journalMOLECULAR NEURODEGENERATION-
dc.contributor.googleauthorLim, Su Min-
dc.contributor.googleauthorChoi, Won Jun-
dc.contributor.googleauthorOh, Ki-Wook-
dc.contributor.googleauthorXue, Yuanchao-
dc.contributor.googleauthorChoi, Ji Young-
dc.contributor.googleauthorKim, Sung Hoon-
dc.contributor.googleauthorNahm, Minyeop-
dc.contributor.googleauthorKim, Young-Eun-
dc.contributor.googleauthorLee, Jinhyuk-
dc.contributor.googleauthorNoh, Min-Young-
dc.relation.code2016012411-
dc.sector.campusS-
dc.sector.daehakRESEARCH INSTITUTE[S]-
dc.sector.departmentINSTITUTE OF MEDICAL SCIENCE-
dc.identifier.pidnmy-


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