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.; Vendruscolo, Michele; Mann, Matthias; Hartl, F. Ulrich

doi:10.1016/j.cell.2016.12.041

Cited by 135 publications

(249 citation statements)

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“…The ageassociated increase in SQST-1, which is the C. elegans homologue of the elegans autophagosome cargo protein p62, also supports a late-life dysfunctional autophagic machinery in worms. This is also in agreement with the widespread protein aggregation during C. elegans ageing [60,61]. We additionally noted that genes crucially involved in the late autophagic flux at the steps of autolysosome formation and degradation are dispensable in aged worms.…”

Section: Age-related Changes In Autophagysupporting

confidence: 88%

“…A recent proteomic study revealed that daf-2 mutants employ enhanced 'waste management' strategies with age. Compared to aged WT worms, autophagy is neither systematically upregulated nor functionally enhanced in aged daf-2 mutants [59,60]. In contrast, daf-2 mutants enhance the UPS earlier and more pronounced during ageing than their WT counterpart [60].…”

Section: Regulation Of Autophagy In Longevitymentioning

confidence: 80%

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Autophagy during ageing – from Dr Jekyll to Mr Hyde

Wilhelm

Richly

2018

The FEBS Journal

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Autophagy is a ubiquitous catabolic process, which causes cellular bulk degradation through vesicular engulfment of obsolete, damaged or harmful cytoplasmic components. While autophagy regulates cellular homeostasis during development and in youth, there is mounting evidence that autophagy becomes increasingly dysfunctional with age. Recent work in Caenorhabditis elegans even suggests that late‐life dysfunctional autophagy exhibits detrimental effects that drive the ageing process. Other studies link elevated autophagy closely to increased health and longevity. This review aims to put these apparently opposing views into perspective and define our current understanding of the role of autophagy during ageing.

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Section: Age-related Changes In Autophagysupporting

confidence: 88%

Section: Regulation Of Autophagy In Longevitymentioning

confidence: 80%

Autophagy during ageing – from Dr Jekyll to Mr Hyde

Wilhelm

Richly

2018

The FEBS Journal

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“…Indeed, it has been recently shown that sequestering proteins into chaperone‐enriched aggregates prevents an age‐related decline in proteostasis and prolongs lifespan in C. elegans (Walther et al . ). Thus, HSPs may play an active role in the formation of the inclusions, rather than merely being a part of them as a fall‐out of their formation.…”

Section: The Role Of Molecular Chaperones In Neurodegenerative Diseasementioning

confidence: 97%

Walking the tightrope: proteostasis and neurodegenerative disease

Yerbury

Ooi

Dillin

et al. 2016

Journal of Neurochemistry

199

146

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A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid-b, a-synuclein, or superoxide dismutase1 (SOD1), many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration, and location to be functional. In this review, we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degra-

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“…It is commonly thought that an age‐related impairment of protein degradation affects general proteostasis networks, causing enhanced accumulation of damaged proteins that can be cytotoxic and shortens lifespan . During aging, the cellular proteostasis network shows significant changes in expression, mainly causing an overall reduction in protein synthesis, which reflects age‐dependent remodeling of an imbalanced proteome . Progressive decline of proteostasis can lead to the development of various diseases .…”

Section: Discussionmentioning

confidence: 99%

Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

2017

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Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves folding and degradation of damaged proteins, and is essential for cellular function, organismal growth, and viability 1, 2. Misfolded proteins that cannot be refolded by chaperone machineries are degraded by specialized proteolytic systems. A major degradation pathway regulating cellular proteostasis is the ubiquitin (Ub)/proteasome system (UPS), which regulates turnover of damaged proteins that accumulate upon stress and during aging. Despite a large number of structurally unrelated substrates, Ub conjugation is remarkably selective. Substrate selectivity is mainly provided by the group of E3 enzymes. Several observations indicate that numerous E3 Ub ligases intimately collaborate with molecular chaperones to maintain the cellular proteome. In this review, we provide an overview of specialized quality control E3 ligases playing a critical role in the degradation of damaged proteins. The process of substrate recognition and turnover, the type of chaperones they team up with, and the potential pathogeneses associated with their malfunction will be further discussed.

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Widespread Proteome Remodeling and Aggregation in Aging C. elegans

Cited by 135 publications

References 0 publications

Autophagy during ageing – from Dr Jekyll to Mr Hyde

Autophagy during ageing – from Dr Jekyll to Mr Hyde

Walking the tightrope: proteostasis and neurodegenerative disease

Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

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