Preferential Involvement of BRCA1/BARD1, Not Tip60/Fe65, in DNA Double-Strand Break Repair in Presenilin-1 P117L Alzheimer Models

Article Article scientifique Article Preferential Involvement of BRCA1/BARD1, Not Tip60/Fe65, in DNA Double-Strand Break Repair in Presenilin-1 P117L Alzheimer Models eng 2022-02-21 author Maciel Authiat Marcella 982971 author Gruz-Gibelli Emmanuelle author Colas Julien 844025 author Bianchi Estelle 502525 author Garcia Arauzo Marta 0000-0001-8656-2538 967607 author Marin Pascale 22116 author Herrmann François 70980 author Savioz Armand 0000-0001-8059-8281 135243 3172861 10.1155/2022/3172861 35237315 1687-5443 PMC8885292 https://www.hindawi.com/journals/np/2022/3172861 Recently, we showed that DNA double-strand breaks (DSBs) are increased by the Aβ42-amyloid peptide and decreased by all-trans retinoic acid (RA) in SH-SY5Y cells and C57BL/6J mice. The present work was aimed at investigating DSBs in cells and murine models of Alzheimer’s disease carrying the preseniline-1 (PS1) P117L mutation. We observed that DSBs could hardly decrease following RA treatment in the mutated cells compared to the wild-type cells. The activation of the amyloidogenic pathway is proposed in the former case as Aβ42- and RA-dependent DSBs changes were reproduced by an α-secretase and a γ-secretase inhibitions, respectively. Unexpectedly, the PS1 P117L cells showed lower DSB levels than the controls. As the DSB repair proteins Tip60 and Fe65 were less expressed in the mutated cell nuclei, they do not appear to contribute to this difference. On the contrary, full-length BRCA1 and BARD1 proteins were significantly increased in the chromatin compartment of the mutated cells, suggesting that they decrease DSBs in the pathological situation. These Western blot data were corroborated by in situ proximity ligation assays: the numbers of BRCA1-BARD1, not of Fe65-Tip60 heterodimers, were increased only in the mutated cell nuclei. RA also enhanced the expression of BARD1 and of the 90 kDa BRCA1 isoform. The increased BRCA1 expression in the mutated cells can be related to the enhanced difficulty to inhibit this pathway by BRCA1 siRNA in these cells. Overall, our study suggests that at earlier stages of the disease, similarly to PS1 P117L cells, a compensatory mechanism exists that decreases DSB levels via an activation of the BRCA1/BARD1 pathway. This supports the importance of this pathway in neuroprotection against Alzheimer’s disease. Dewey 616.8 Dewey 616.89 Dewey 590 Dewey 618.97 16 Centre interfacultaire de neurosciences 0D9 44 Département de génétique et évolution 162 60 Département de psychiatrie 225 65 Département de réadaptation et gériatrie 22B false 1221 Neuroimagerie moléculaire en psychiatrie 983 Neural plasticity 2022 3bb893e8-a49b-4229-8c2d-cfdd2c71463b Article (Published version) Public Authiat et al.pdf 2914123 application/pdf CC BY-4.0 openAccess Centres et instituts / Centre interfacultaire de neurosciences Faculté des sciences / Section de biologie / Département de génétique et évolution Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de médecine / Section de médecine clinique / Département de réadaptation et gériatrie

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Preferential Involvement of BRCA1/BARD1, Not Tip60/Fe65, in DNA Double-Strand Break Repair in Presenilin-1 P117L Alzheimer Models	Neural plasticity			2022	260	107

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Maciel Authiat, Marcella