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Overactive BRCA1 Af...
Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease
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- Wezyk, Michalina (author)
- Umeå universitet,Klinisk neurovetenskap
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Szybinska, Aleksandra (author)
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Wojsiat, Joanna (author)
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Szczerba, Marcelina (author)
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Day, Kelly (author)
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Ronnholm, Harriet (author)
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Kele, Malin (author)
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- Berdynski, Mariusz (author)
- Umeå universitet,Klinisk neurovetenskap,Department of Neurodegenerative Disorders, Laboratory of Neurogenetics, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland
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Peplonska, Beata (author)
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Fichna, Jakub Piotr (author)
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Ilkowski, Jan (author)
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Styczynska, Maria (author)
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Barczak, Anna (author)
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Zboch, Marzena (author)
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Filipek-Gliszczynska, Anna (author)
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Bojakowski, Krzysztof (author)
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Skrzypczak, Magdalena (author)
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Ginalski, Krzysztof (author)
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Kabza, Michal (author)
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Makalowska, Izabela (author)
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Barcikowska-Kotowicz, Maria (author)
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Wojda, Urszula (author)
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- Falk, Anna (author)
- Karolinska Institutet
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Zekanowski, Cezary (author)
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(creator_code:org_t)
- IOS Press, 2018
- 2018
- English.
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 62:1, s. 175-202
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- Alzheimer's disease
- BRCA1
- DNA damage response
- cell cycle re-entry
- presenilin 1
- ubiquitination
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Wezyk, Michalina
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Szybinska, Aleks ...
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Wojsiat, Joanna
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Szczerba, Marcel ...
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Day, Kelly
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Ronnholm, Harrie ...
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show more...
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Kele, Malin
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Berdynski, Mariu ...
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Peplonska, Beata
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Fichna, Jakub Pi ...
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Ilkowski, Jan
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Styczynska, Mari ...
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Barczak, Anna
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Zboch, Marzena
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Filipek-Gliszczy ...
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Bojakowski, Krzy ...
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Skrzypczak, Magd ...
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Ginalski, Krzysz ...
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Kabza, Michal
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Makalowska, Izab ...
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Barcikowska-Koto ...
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Wojda, Urszula
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Falk, Anna
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Zekanowski, Ceza ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
- Articles in the publication
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Journal of Alzhe ...
- By the university
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Umeå University
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Karolinska Institutet