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Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease
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2018 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 62, no 1, p. 175-202Article in journal (Refereed) Published
Abstract [en]

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-beta. 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-beta pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Place, publisher, year, edition, pages
IOS Press, 2018. Vol. 62, no 1, p. 175-202
Keywords [en]
Alzheimer's disease, BRCA1, DNA damage response, cell cycle re-entry, presenilin 1, ubiquitination
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-145170DOI: 10.3233/JAD-170830ISI: 000424245200014PubMedID: 29439343OAI: oai:DiVA.org:umu-145170DiVA, id: diva2:1185317
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-06-09Bibliographically approved

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Berdynski, Mariusz

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Department of Pharmacology and Clinical Neuroscience
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CiteExportLink to record
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