<br>PS1 突变型 N2a 细胞对细胞应激的敏感性与线粒体缺陷和钙稳态改变有关。,Scientific Reports

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PS1 突变型 N2a 细胞对细胞应激的敏感性与线粒体缺陷和钙稳态改变有关。
Scientific Reports ( IF 3.8 ) Pub Date : 2020-04-15 , DOI: 10.1038/s41598-020-63254-7
Liliana Rojas-Charry ₁ , Sergio Calero-Martinez ₁ , Claudia Morganti ₂ , Giampaolo Morciano ₂ , Kyungeun Park ₁ , Christian Hagel ₁ , Stefan J Marciniak ₃ , Markus Glatzel ₁ , Paolo Pinton ₂ , Diego Sepulveda-Falla ₁

Affiliation

早老素 1 (PS1) 突变是家族性阿尔茨海默病 (FAD) 的最常见原因。 PS1 还在钙稳态和自噬等细胞过程中发挥作用。我们假设突变的早老素会增加细胞对压力的脆弱性。我们在小鼠神经母细胞瘤 N2a 细胞中稳定表达人 PS1、突变型 PS1E280A 和突变型 PS1Δ9。我们检查了不同条件下应激的早期迹象：内质网 (ER) 应激、钙超载、氧化应激和 Aβ 1-42 寡聚物毒性。此外，我们通过血清饥饿诱导自噬。 PS1 突变对 ER 应激没有影响，但 PS1E280A 突变影响自噬。 PS1 过度表达影响钙稳态并产生线粒体钙超载，从而改变线粒体功能。然而，线粒体通透性转换孔（MPTP）的开放在 PS1 突变体中受到影响，在 PS1E280A 中加速，在 PS1Δ9 细胞中受到抑制。 PS1E280A 细胞中改变的自噬既不能通过抑制 γ 分泌酶来改变，也不能通过 ER 钙保留来改变。 MPTP 的开放由 γ-分泌酶抑制剂直接调节，不依赖于细胞器钙调节，这表明 PS1 和 γ-分泌酶在线粒体应激中具有新的直接作用。我们发现 PS1 突变体对应激的内在细胞脆弱性与自噬和线粒体功能同时相关，与 Aβ 病理无关。

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Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis.

Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma N2a cells. We examined early signs of stress in different conditions: endoplasmic reticulum (ER) stress, calcium overload, oxidative stress, and Aβ 1-42 oligomers toxicity. Additionally, we induced autophagy via serum starvation. PS1 mutations did not have an effect in ER stress but PS1E280A mutation affected autophagy. PS1 overexpression influenced calcium homeostasis and generated mitochondrial calcium overload modifying mitochondrial function. However, the opening of the mitochondrial permeability transition pore (MPTP) was affected in PS1 mutants, being accelerated in PS1E280A and inhibited in PS1Δ9 cells. Altered autophagy in PS1E280A cells was neither modified by inhibition of γ-secretase, nor by ER calcium retention. MPTP opening was directly regulated by γ-secretase inhibitors independent on organelle calcium modulation, suggesting a novel direct role for PS1 and γ-secretase in mitochondrial stress. We identified intrinsic cellular vulnerability to stress in PS1 mutants associated simultaneously with both, autophagic and mitochondrial function, independent of Aβ pathology.

更新日期：2020-04-24

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