PMID- 37804602
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20231023
IS  - 1568-7856 (Electronic)
IS  - 1568-7856 (Linking)
VI  - 131
DP  - 2023 Nov
TI  - Presenilin-1, mutated in familial Alzheimer's disease, maintains genome stability 
      via a gamma-secretase dependent way.
PG  - 103580
LID - S1568-7864(23)00134-9 [pii]
LID - 10.1016/j.dnarep.2023.103580 [doi]
AB  - 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 beta (Abeta) was able to 
      induce GIN, PS1-KD was associated with decreased expression of Abeta in SH-SY5Y 
      cells, suggesting Abeta is not the primary cause of GIN in PS1-KD cells. In 
      contrast, inhibiting the PS1 gamma-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 gamma-secretase activity. PS1 KD or 
      gamma-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 gamma-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.
CI  - Copyright (c) 2023 Elsevier B.V. All rights reserved.
FAU - Guo, Xihan
AU  - Guo X
AD  - School of Life Sciences, Yunnan Normal University, Kunming, Yunnan 650500, China; 
      The Engineering Research Center of Sustainable Development and Utilization of 
      Biomass Energy, Yunnan Normal University, Kunming, Yunnan 650500, China. 
      Electronic address: guo_xihan@163.com.
FAU - Jiang, Minyan
AU  - Jiang M
AD  - School of Life Sciences, Yunnan Normal University, Kunming, Yunnan 650500, China.
FAU - Dai, Xueqin
AU  - Dai X
AD  - Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, 
      China.
FAU - Shen, Jie
AU  - Shen J
AD  - School of Life Sciences, Yunnan Normal University, Kunming, Yunnan 650500, China.
FAU - Wang, Xu
AU  - Wang X
AD  - School of Life Sciences, Yunnan Normal University, Kunming, Yunnan 650500, China; 
      The Engineering Research Center of Sustainable Development and Utilization of 
      Biomass Energy, Yunnan Normal University, Kunming, Yunnan 650500, China; Yeda 
      Institute of Gene and Cell Therapy, Taizhou, Zhejiang 318000, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230930
PL  - Netherlands
TA  - DNA Repair (Amst)
JT  - DNA repair
JID - 101139138
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Presenilin-1)
SB  - IM
MH  - Humans
MH  - *Alzheimer Disease/genetics/metabolism
MH  - Amyloid Precursor Protein Secretases/genetics/metabolism
MH  - Amyloid beta-Peptides/genetics/metabolism
MH  - Presenilin-1/genetics/metabolism
MH  - *Neuroblastoma
MH  - Mutation
MH  - Genomic Instability
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Gain-of-function mutation
OT  - Genome instability
OT  - Loss-of-function mutation
OT  - Presenilins
COIS- Declaration of Competing Interest The authors state that they no known competing 
      interests.
EDAT- 2023/10/08 02:42
MHDA- 2023/10/23 01:18
CRDT- 2023/10/07 18:04
PHST- 2023/05/08 00:00 [received]
PHST- 2023/09/26 00:00 [revised]
PHST- 2023/09/29 00:00 [accepted]
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/10/08 02:42 [pubmed]
PHST- 2023/10/07 18:04 [entrez]
AID - S1568-7864(23)00134-9 [pii]
AID - 10.1016/j.dnarep.2023.103580 [doi]
PST - ppublish
SO  - DNA Repair (Amst). 2023 Nov;131:103580. doi: 10.1016/j.dnarep.2023.103580. Epub 
      2023 Sep 30.