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

Article type: Research Article

Authors: Wezyk, Michalina^{a; *} | Szybinska, Aleksandra^a | Wojsiat, Joanna^b | Szczerba, Marcelina^a | Day, Kelly^c | Ronnholm, Harriet^c | Kele, Malin^c | Berdynski, Mariusz^{a; d} | Peplonska, Beata^a | Fichna, Jakub Piotr^a | Ilkowski, Jan^e | Styczynska, Maria^a | Barczak, Anna^a | Zboch, Marzena^f | Filipek-Gliszczynska, Anna^g | Bojakowski, Krzysztof^h | Skrzypczak, Magdalenaⁱ | Ginalski, Krzysztofⁱ | Kabza, Michal^j | Makalowska, Izabela^j | Barcikowska-Kotowicz, Maria^a | Wojda, Urszula^b | Falk, Anna^c | Zekanowski, Cezary^a

Affiliations: [a] Department of Neurodegenerative Disorders, Laboratory of Neurogenetics, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland | [b] Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Warsaw, Poland | [c] Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden | [d] Department of Pharmacology and Clinical Neuroscience, Umea Universitet, Umea, Sweden | [e] Department of Emergency Medicine, Faculty of Health Sciences, Poznan University of Medical Sciences, Poznan, Poland | [f] Center of Alzheimer’s Disease of Wroclaw Medical University, Scinawa, Poland | [g] Clinical Department of Neurology, Extrapyramidal Disorders and Alzheimer’s Outpatient Clinic, Central Clinical Hospital of the Ministry of the Interior and Administration in Warsaw, Warsaw, Poland | [h] Clinical Department of General and Vascular Surgery, Central Clinical Hospital of the Ministry of the Interior and Administration in Warsaw, Warsaw, Poland | [i] Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Warsaw, Poland | [j] Department of Integrated Genomics, Institute of Anthropology, Adam Mickiewicz University, Poznan, Poland

Correspondence: [*] Correspondence to: Michalina Wezyk, Department of Neurodegenerative Disorders, Laboratory of Neurogenetics, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland. E-mail: [email protected].

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) 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.

Keywords: Alzheimer’s disease, BRCA1, DNA damage response, cell cycle re-entry, presenilin 1, ubiquitination

DOI: 10.3233/JAD-170830

Journal: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 175-202, 2018