TY - JOUR
T1 - Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease
AU - Wezyk, Michalina
AU - Szybinska, Aleksandra
AU - Wojsiat, Joanna
AU - Szczerba, Marcelina
AU - Day, Kelly
AU - Ronnholm, Harriet
AU - Kele, Malin
AU - Berdynski, Mariusz
AU - Peplonska, Beata
AU - Fichna, Jakub Piotr
AU - Ilkowski, Jan
AU - Styczynska, Maria
AU - Barczak, Anna
AU - Zboch, Marzena
AU - Filipek-Gliszczynska, Anna
AU - Bojakowski, Krzysztof
AU - Skrzypczak, Magdalena
AU - Ginalski, Krzysztof
AU - Kabza, Michal
AU - Makalowska, Izabela
AU - Barcikowska-Kotowicz, Maria
AU - Wojda, Urszula
AU - Falk, Anna
AU - Zekanowski, Cezary
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Alzheimer Disease/genetics
KW - Amyloid beta-Peptides/metabolism
KW - BRCA1 Protein/metabolism
KW - Cells, Cultured
KW - Cellular Reprogramming Techniques
KW - Computational Biology
KW - Fibroblasts/metabolism
KW - Gene Expression
KW - Humans
KW - Induced Pluripotent Stem Cells/metabolism
KW - Nerve Degeneration/genetics
KW - Neurons/metabolism
KW - Phosphorylation
KW - Presenilin-1/genetics
KW - Presenilin-2/genetics
KW - Signal Transduction
KW - Transcriptome
KW - cdc25 Phosphatases/metabolism
U2 - 10.3233/JAD-170830
DO - 10.3233/JAD-170830
M3 - Article
C2 - 29439343
SN - 1387-2877
VL - 62
SP - 175
EP - 202
JO - Journal of Alzheimer's disease : JAD
JF - Journal of Alzheimer's disease : JAD
IS - 1
ER -