Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease
(2018) In Journal of Alzheimer's disease : JAD 62(1). p.175-202- Abstract
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)... (More)
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.
(Less)
- author
- publishing date
- 2018
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer Disease/genetics, Amyloid beta-Peptides/metabolism, BRCA1 Protein/metabolism, Cells, Cultured, Cellular Reprogramming Techniques, Computational Biology, Fibroblasts/metabolism, Gene Expression, Humans, Induced Pluripotent Stem Cells/metabolism, Nerve Degeneration/genetics, Neurons/metabolism, Phosphorylation, Presenilin-1/genetics, Presenilin-2/genetics, Signal Transduction, Transcriptome, cdc25 Phosphatases/metabolism
- in
- Journal of Alzheimer's disease : JAD
- volume
- 62
- issue
- 1
- pages
- 175 - 202
- publisher
- IOS Press
- external identifiers
-
- scopus:85047111538
- pmid:29439343
- ISSN
- 1387-2877
- DOI
- 10.3233/JAD-170830
- language
- English
- LU publication?
- no
- id
- b183baf0-7da6-448b-9062-712551361387
- date added to LUP
- 2021-08-09 16:27:33
- date last changed
- 2024-10-06 02:14:50
@article{b183baf0-7da6-448b-9062-712551361387,
abstract = {{<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>}},
author = {{Wezyk, Michalina and Szybinska, Aleksandra and Wojsiat, Joanna and Szczerba, Marcelina and Day, Kelly and Ronnholm, Harriet and Kele, Malin and Berdynski, Mariusz and Peplonska, Beata and Fichna, Jakub Piotr and Ilkowski, Jan and Styczynska, Maria and Barczak, Anna and Zboch, Marzena and Filipek-Gliszczynska, Anna and Bojakowski, Krzysztof and Skrzypczak, Magdalena and Ginalski, Krzysztof and Kabza, Michal and Makalowska, Izabela and Barcikowska-Kotowicz, Maria and Wojda, Urszula and Falk, Anna and Zekanowski, Cezary}},
issn = {{1387-2877}},
keywords = {{Alzheimer Disease/genetics; Amyloid beta-Peptides/metabolism; BRCA1 Protein/metabolism; Cells, Cultured; Cellular Reprogramming Techniques; Computational Biology; Fibroblasts/metabolism; Gene Expression; Humans; Induced Pluripotent Stem Cells/metabolism; Nerve Degeneration/genetics; Neurons/metabolism; Phosphorylation; Presenilin-1/genetics; Presenilin-2/genetics; Signal Transduction; Transcriptome; cdc25 Phosphatases/metabolism}},
language = {{eng}},
number = {{1}},
pages = {{175--202}},
publisher = {{IOS Press}},
series = {{Journal of Alzheimer's disease : JAD}},
title = {{Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease}},
url = {{http://dx.doi.org/10.3233/JAD-170830}},
doi = {{10.3233/JAD-170830}},
volume = {{62}},
year = {{2018}},
}