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Presenilin-1, mutated in familial Alzheimer's disease, maintains genome stability via a γ-secretase dependent way.

Authors :
Guo, Xihan
Jiang, Minyan
Dai, Xueqin
Shen, Jie
Wang, Xu
Source :
DNA Repair. Nov2023, Vol. 131, pN.PAG-N.PAG. 1p.
Publication Year :
2023

Abstract

Mutations in Presenilin-1 (PS1) account for over 80 % mutations linked to familial Alzheimer's disease (AD). However, the mechanisms of action of PS1 mutations in causing familial AD are not fully understood, limiting opportunities to develop targeted disease-modifying therapies for individuals carrying PS1 mutation. To gain more comprehensive insights into the impact of PS1 mutations on genome stability, we knocked down PS1 in SH-SY5Y, HMC3 and A549 cells. This revealed that PS1 knockdown (KD) dramatically induces genome instability (GIN) in all cell types, as indicated by the increased incidence of micronuclei, nucleoplasmic bridges and/or nuclear buds. Although amyloid β (Aβ) was able to induce GIN, PS1-KD was associated with decreased expression of Aβ in SH-SY5Y cells, suggesting Aβ is not the primary cause of GIN in PS1-KD cells. In contrast, inhibiting the PS1 γ-secretase activity by DAPT recapitulated GIN phenotype as seen in PS1-KD cells, indicating that the induction of GIN following PS1 KD can be attributed to the loss of γ-secretase activity. PS1 KD or γ-secretase inhibition markedly sensitizes SH-SY5Y to the genotoxicity of mitomycin C. Interestingly, overexpression of the wildtype PS1 dramatically increased GIN in SH-SY5Y. Collectively, our study demonstrates the potential of PS1 and its γ-secretase activity in maintaining genome stability, highlighting a novel potential link between PS1 loss-of-function or gain-of-function mutations and familial AD through GIN. Several mechanisms by which GIN induced by PS1 dys-expression may contribute to AD are discussed. • PS1 KD increase the rate of GIN in SH-SY5Y, A549 and HMC3 cells. • GIN induced from PS1-KD is not mediated by Aβ accumulation. • Loss of γ-secretase activity maybe involved in PS1-KD induced GIN. • γ-secretase inhibition or PS1 KD exacerbates mutagen-induced GIN. • PS1 over-expression induces GIN in SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15687864
Volume :
131
Database :
Academic Search Index
Journal :
DNA Repair
Publication Type :
Academic Journal
Accession number :
173011209
Full Text :
https://doi.org/10.1016/j.dnarep.2023.103580