Abstract
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.
Highlights
The maintenance of a highly functional proteome is critical for organismal health
Using Caenorhabditis elegans as a model system to understand presenilin function, we found that mutations in the C. elegans presenilin gene cause elevated endoplas‐ mic reticulum (ER) to mitochondria calcium signaling, which leads to an increase in mitochondrial calcium content that results in increased mito‐ chondrial oxidative phosphorylation and electron leak accelerat‐ ing oxidative stress (Sarasija et al, 2018)
When these animals reach day 5 of adulthood, aggrega‐ tion of Q35::YFP is readily apparent (Figure 1b,c). We introduced this transgene into three sel‐12 mutants, sel‐12(ar131), sel‐12(ok2078), and sel‐12(ty11). sel‐12(ar131) mutants carry a missense mutation in the sel‐12 gene that changes a cysteine to a tyrosine (C60Y), which is a conserved change observed in human presenilin that is associated with Familial AD (FAD) (Levitan & Greenwald, 1995), sel‐12(ok2078) mutants have a large deletion of the sel‐12 locus and sel‐12(ty11) mutants contain a premature stop codon in the sel‐12 open reading frame (Cinar, Sweet, Hosemann, Earley, & Newman, 2001) (Figure 1a)
Summary
The maintenance of a highly functional proteome is critical for organismal health. This is important in the aging ner‐ vous system. Since calcium is known to stimulate mitochondrial respiration (Llorente‐Folch et al, 2015;Tarasov, Griffiths, & Rutter, 2012) and we previously demonstrated that elevated ER to mitochondria cal‐ cium signaling in sel‐12 mutants leads to increased mitochondrial re‐ active oxygen species (ROS) production via electron leak caused by increased mitochondrial respiration (Sarasija et al, 2018), we sought to determine whether the proteostasis defects observed in sel‐12 mutants is caused by oxidative stress, a known inducer of proteo‐ stasis dysfunction (Korovila et al, 2017) Consistent with this notion, we previously found that antioxidant supplementation prevented sel‐12 neurodegenerative phenotypes (Sarasija et al, 2018). Analysis of LGG‐1::GFP in day 1 adults revealed a slight but significant decrease in autophagosome number in sel‐12 mutants compared with aged wild‐type animals (Figure 6c,d) These data suggest that sel‐12 mutants have reduced autophagy and this along with the mitochondrial generated oxidative stress likely exacerbates the collapse of proteostasis ob‐ served in sel‐12 mutants
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