Corrupted ER-mitochondrial calcium homeostasis promotes the collapse of proteostasis.,Aging Cell

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Corrupted ER-mitochondrial calcium homeostasis promotes the collapse of proteostasis.
Aging Cell ( IF 8.0 ) Pub Date : 2019-11-12 , DOI: 10.1111/acel.13065
Zahra Ashkavand ₁ , Shaarika Sarasija ₁ , Kerry C Ryan ₁ , Jocelyn T Laboy ₁ , Kenneth R Norman ₁

Affiliation

Aging and age‐related diseases are associated with a decline of protein homeostasis (proteostasis), but the mechanisms underlying this decline are not clear. In particular, decreased proteostasis is a widespread molecular feature of neurodegenerative diseases, such as Alzheimer's disease (AD). Familial AD is largely caused by mutations in the presenilin encoding genes; however, their role in AD is not understood. In this study, we investigate the role of presenilins in proteostasis using the model system Caenorhabditis elegans. Previously, we found that mutations in C. elegans presenilin cause elevated ER to mitochondria calcium signaling, which leads to an increase in mitochondrial generated oxidative stress. This, in turn, promotes neurodegeneration. To understand the cellular mechanisms driving neurodegeneration, using several molecular readouts of protein stability in C. elegans, we find that presenilin mutants have widespread defects in proteostasis. Markedly, we demonstrate that these defects are independent of the protease activity of presenilin and that reduction in ER to mitochondrial calcium signaling can significantly prevent the proteostasis defects observed in presenilin mutants. Furthermore, we show that supplementing presenilin mutants with antioxidants suppresses the proteostasis defects. Our findings indicate that defective ER to mitochondria calcium signaling promotes proteostatic collapse in presenilin mutants by increasing oxidative stress.

中文翻译：

内质网线粒体钙稳态的破坏会促进蛋白质稳态的崩溃。

衰老和与年龄相关的疾病与蛋白质稳态（蛋白质稳态）的下降有关，但这种下降的机制尚不清楚。特别是，蛋白质稳态降低是神经退行性疾病（例如阿尔茨海默氏病（AD））的普遍分子特征。家族性 AD 主要是由早老素编码基因突变引起的。然而，它们在 AD 中的作用尚不清楚。在这项研究中，我们使用秀丽隐杆线虫模型系统研究了早老素在蛋白质稳态中的作用。此前，我们发现秀丽隐杆线虫早老素的突变导致线粒体钙信号传导的ER升高，从而导致线粒体产生的氧化应激增加。这反过来又会促进神经退行性变。为了了解驱动神经退行性变的细胞机制，使用线虫中蛋白质稳定性的几种分子读数，我们发现早老素突变体在蛋白质稳态方面存在广泛的缺陷。值得注意的是，我们证明这些缺陷与早老素的蛋白酶活性无关，并且减少 ER 对线粒体钙信号传导可以显着防止在早老素突变体中观察到的蛋白质稳态缺陷。此外，我们发现用抗氧化剂补充早老素突变体可以抑制蛋白质稳态缺陷。我们的研究结果表明，线粒体钙信号传导缺陷的 ER 通过增加氧化应激，促进早老素突变体中的蛋白质抑制崩溃。

更新日期：2019-11-12

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