Widespread Proteome Remodeling and Aggregation in Aging C. elegans

Walther, Dirk; Kasturi, Prasad; Zheng, Min; Pinkert, Stefan; Vecchi, Giulia; Ciryam, Prajwal; Morimoto, Richard I.; Dobson, Christopher M.; Mann, Matthias; Hartl, F. Ulrich

doi:10.1016/j.cell.2015.03.032

Cited by 505 publications

(513 citation statements)

References 87 publications

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“…We now show that two other small HSP members that have activities on only one of the two substrates investigated here, one related to acute stress (CG14207) and one to chronic stress (HSP67Bc), also are capable of extending lifespan in Drosophila , demonstrating that increased levels of functionally diverse small HSPs can promote longevity in vivo by different protective activities that yet both contribute to an improved protein homeostasis. Notably, a recent extensive study on proteome remodeling and aggregation in aging C. elegans (Walther et al ., 2015) showed that among all chaperones, particularly small HSPs were associated with the increase in protein homeostasis in long‐lived daf‐2 mutant worms, consistent with the view that small HSPs play a pivotal role in the lifespan‐prolonging effect of the insulin/insulin‐like growth factor‐1 signaling pathway.…”

Section: Discussionsupporting

confidence: 70%

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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SummaryDuring aging, oxidized, misfolded, and aggregated proteins accumulate in cells, while the capacity to deal with protein damage declines severely. To cope with the toxicity of damaged proteins, cells rely on protein quality control networks, in particular proteins belonging to the family of heat‐shock proteins (HSPs). As safeguards of the cellular proteome, HSPs assist in protein folding and prevent accumulation of damaged, misfolded proteins. Here, we compared the capacity of all Drosophila melanogaster small HSP family members for their ability to assist in refolding stress‐denatured substrates and/or to prevent aggregation of disease‐associated misfolded proteins. We identified CG14207 as a novel and potent small HSP member that exclusively assisted in HSP70‐dependent refolding of stress‐denatured proteins. Furthermore, we report that HSP67BC, which has no role in protein refolding, was the most effective small HSP preventing toxic protein aggregation in an HSP70‐independent manner. Importantly, overexpression of both CG14207 and HSP67BC in Drosophila leads to a mild increase in lifespan, demonstrating that increased levels of functionally diverse small HSPs can promote longevity in vivo.

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Section: Discussionsupporting

confidence: 70%

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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“…Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This concept of aggregates as a form of cell protection might also apply to amyloid plaques, which are protein aggregates folded into fibrils to allow for many copies of the aberrant protein within a cell.…”

mentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…To illustrate how the CNV approach can provide novel biological insights, we analyzed a time‐series mass spectrometry experiment related to aging of C. elegans (Walther et al , 2015). The abundance of proteins was calculated at five different time points during the lifespan of the organism (days 1, 6, 12, 17, and 22) using the SILAC approach (Ong et al , 2002).…”

Section: Resultsmentioning

confidence: 99%

“… Analysis of the abundance distribution for (A) cytoplasmic, (B) mitochondrial, and (C) extracellular proteins across five age groups in C. elegans (Walther et al , 2015). Each age group was compared against a pool reference sample using SILAC (Ong et al , 2002).…”

Section: Resultsmentioning

confidence: 99%

“…Conversely, we observed that proteins forming the inner and outer mitochondrial membrane transport systems increase their abundance with age (Mann–Whitney test P = 3.9 × 10 −3 ; Fig 3D). This phenomenon might be linked to protein turnover imbalances in the mitochondrion and the age‐related increase in harmful and damaged proteins in the organelle (Walther et al , 2015). These results indicate that the mitochondrial proteome, as a whole, decreases during aging, and the variation in the abundance of specific proteins hints to re‐arrangement of mitochondria composition potentially underlying ultrastructural differences (Brandt et al , 2017).…”

Section: Resultsmentioning

confidence: 99%

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Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

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Widespread Proteome Remodeling and Aggregation in Aging C. elegans

Cited by 505 publications

References 87 publications

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Proteostasis in cardiac health and disease

Quantifying compartment‐associated variations of protein abundance in proteomics data

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