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Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease

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dc.abstract.en<p>The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.</p>
dc.affiliationUniwersytet Warszawski
dc.contributor.authorSzczerba, Marcelina
dc.contributor.authorMakałowska, Izabela
dc.contributor.authorDay, Kelly
dc.contributor.authorFalk, Anna
dc.contributor.authorRonnholm, Harriet
dc.contributor.authorKele, Malin
dc.contributor.authorKabza, Michal
dc.contributor.authorZboch, Marzena
dc.contributor.authorFilipek-Gliszczynska, Anna
dc.contributor.authorBarczak, Anna
dc.contributor.authorWojda, Urszula
dc.contributor.authorPodgórska, Joanna
dc.contributor.authorBarcikowska-Kotowicz, Maria
dc.contributor.authorBerdyński, Mariusz
dc.contributor.authorBorzemska, Beata
dc.contributor.authorFichna, Jakub
dc.contributor.authorŻekanowski, Cezary
dc.contributor.authorIlkowski, Jan
dc.contributor.authorBojakowski, Krzysztof
dc.contributor.authorSkrzypczak, Magdalena
dc.contributor.authorWężyk, Michalina
dc.contributor.authorGinalski, Krzysztof
dc.contributor.authorSzybińska, Aleksandra
dc.contributor.authorStyczyńska, Maria
dc.date.accessioned2024-01-25T16:10:07Z
dc.date.available2024-01-25T16:10:07Z
dc.date.issued2018
dc.description.financeNie dotyczy
dc.description.number1
dc.description.volume62
dc.identifier.doi10.3233/JAD-170830
dc.identifier.issn1387-2877
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/115134
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofJournal of Alzheimer's Disease
dc.relation.pages175-202
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleOveractive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease
dc.typeJournalArticle
dspace.entity.typePublication