dc.date.accessioned | 2020-09-01T18:21:37Z | |
dc.date.available | 2020-09-01T18:21:37Z | |
dc.date.created | 2020-08-27T11:34:22Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Liang, Xiao Kristiansen, Cecilie Katrin Mostafavi, Sepideh Vatne, Guro H. Zantingh, Gina Kianian, Atefeh Tzoulis, Charalampos Høyland, Lena Elise Ziegler, Mathias Perez, Roberto Megias Furriol, Jessica Zhang, Zhuoyuan Balafkan, Novin Hong, Yu Siller, Richard Sullivan, Gareth Bindoff, Laurence . Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations. EMBO Molecular Medicine. 2020 | |
dc.identifier.uri | http://hdl.handle.net/10852/79105 | |
dc.description.abstract | Mutations in POLG disrupt mtDNA replication and cause devas- tating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post-mortem brain tissue. We confirmed the same loss of mtDNA and complex I in dopaminergic neurons generated from the same stem cells. POLG-driven mitochondrial dysfunc- tion led to neuronal ROS overproduction and increased cellular senescence. Loss of complex I was associated with disturbed NAD+ metabolism with increased UCP2 expression and reduced phosphorylated SirT1. In cells with compound heterozygous POLG mutations, we also found activated mitophagy via the BNIP3 pathway. Our studies are the first that show it is possible to recapitulate the neuronal molecular and biochemical defects associated with POLG mutation in a human stem cell model. Further, our data provide insight into how mitochondrial dysfunction and mtDNA alterations influence cellular fate deter- mining processes. | |
dc.language | EN | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations | |
dc.type | Journal article | |
dc.creator.author | Liang, Xiao | |
dc.creator.author | Kristiansen, Cecilie Katrin | |
dc.creator.author | Mostafavi, Sepideh | |
dc.creator.author | Vatne, Guro H. | |
dc.creator.author | Zantingh, Gina | |
dc.creator.author | Kianian, Atefeh | |
dc.creator.author | Tzoulis, Charalampos | |
dc.creator.author | Høyland, Lena Elise | |
dc.creator.author | Ziegler, Mathias | |
dc.creator.author | Perez, Roberto Megias | |
dc.creator.author | Furriol, Jessica | |
dc.creator.author | Zhang, Zhuoyuan | |
dc.creator.author | Balafkan, Novin | |
dc.creator.author | Hong, Yu | |
dc.creator.author | Siller, Richard | |
dc.creator.author | Sullivan, Gareth | |
dc.creator.author | Bindoff, Laurence | |
cristin.unitcode | 185,51,20,10 | |
cristin.unitname | SFF - Hybrid Technology Hub | |
cristin.ispublished | false | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1825487 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=EMBO Molecular Medicine&rft.volume=&rft.spage=&rft.date=2020 | |
dc.identifier.jtitle | EMBO Molecular Medicine | |
dc.identifier.doi | https://doi.org/10.15252/emmm.202012146 | |
dc.identifier.urn | URN:NBN:no-82213 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1757-4676 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/79105/1/emmm.202012146.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | e12146 | |
dc.relation.project | NFR/262613 | |