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.
School of Life Sciences, Yunnan Normal University, Kunming, Yunnan 650500, China.
DNA Repair (Amst). 2023 Nov;131:103580. doi: 10.1016/j.dnarep.2023.103580. Epub 2023 Sep 30.
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.
早老素-1（PS1）突变占家族性阿尔茨海默病（AD）相关突变的 80%以上。然而，PS1 突变导致家族性 AD 的作用机制尚不完全清楚，限制了针对携带 PS1 突变个体的靶向疾病修饰疗法的发展机会。为了更全面地了解 PS1 突变对基因组稳定性的影响，我们在 SH-SY5Y、HMC3 和 A549 细胞中敲低 PS1。结果表明，PS1 敲低（KD）显著诱导所有细胞类型的基因组不稳定性（GIN），表现为微核、核质桥和/或核芽的发生率增加。虽然淀粉样β（Aβ）能够诱导 GIN，但 PS1-KD 与 SH-SY5Y 细胞中 Aβ表达降低有关，表明 Aβ不是 PS1-KD 细胞中 GIN 的主要原因。相比之下，用 DAPT 抑制 PS1 γ-分泌酶活性可再现 PS1-KD 细胞中观察到的 GIN 表型，表明 PS1-KD 后诱导 GIN 可归因于 γ-分泌酶活性的丧失。PS1 KD 或 γ-分泌酶抑制显著增加 SH-SY5Y 对丝裂霉素 C 的遗传毒性敏感性。有趣的是，野生型 PS1 的过表达显著增加了 SH-SY5Y 的 GIN。总之，我们的研究表明 PS1 及其 γ-分泌酶活性在维持基因组稳定性方面的潜力，通过 GIN 突出了 PS1 功能丧失或获得性功能突变与家族性 AD 之间的新潜在联系。讨论了 PS1 表达失调引起的 GIN 可能导致 AD 的几种机制。
