Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans

David, Della; Ollikainen, Noah; Trinidad, Jonathan C.; Cary, Michael; Burlingame, Alma L.; Kenyon, Cynthia

doi:10.1371/journal.pbio.1000450

Cited by 589 publications

(759 citation statements)

References 98 publications

(141 reference statements)

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“…Total aggregate protein far exceeds the sum of IP fractions, as is apparent in Fig. 1A (note lighter exposure for lanes 5 and 6), Table 1, and Supplemental Spreadsheets, reflecting the age‐dependent accrual of protein aggregates even without a pathogenic ‘seed’ protein (David et al ., 2010; Ayyadevara et al ., 2014). However, pronounced AD/NC bias was rare in total aggregates, where it was seen only for apolipoprotein E, neurochondrin, secernin‐1, and tau, with an intermediate shift also evident for filamins A and C, β‐SNAB, and carbonyl reductase.…”

Section: Resultsmentioning

confidence: 99%

“…Total aggregates increase with age in normal C. elegans (David et al ., 2010; Ayyadevara et al ., 2014) and in several tissues of normal mice (Ayyadevara et al ., 2016 and unpublished data), indicating that protein aggregation is a quite broadly conserved feature of aging. In view of our evidence for common processes underlying the growth of both Aβ and tau aggregates, as discussed above, it is surprising that ‘total aggregates’ (sarcosyl‐insoluble material without IP) differed far less between AD and NC than did either type of neuropathological aggregate.…”

Section: Discussionmentioning

confidence: 99%

“…Factors that confer risk for progressive neurodegenerative diseases, although diverse, are all consistent with a simple unifying hypothesis: Protein aggregation leads to neural damage and is exacerbated by aging and other pro‐inflammatory triggers (David et al ., 2010; Dillin & Cohen, 2011). Aggregates are neurotoxic (or more generally cytotoxic) in at least some forms (Bucciantini et al ., 2002); it remains unresolved whether the greater threat is posed by relatively soluble and diffuse aggregates (typically oligomeric) or insoluble, compact conglomerates (Tai et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Aggregates are neurotoxic (or more generally cytotoxic) in at least some forms (Bucciantini et al ., 2002); it remains unresolved whether the greater threat is posed by relatively soluble and diffuse aggregates (typically oligomeric) or insoluble, compact conglomerates (Tai et al ., 2013). Protein aggregates have been shown to form even during normal aging of nematodes (David et al ., 2010; Ayyadevara et al ., 2014). Postsynthetic modifications such as hyperphosphorylation (Rudrabhatla et al ., 2011) and oxidation (Boyd‐Kimball et al ., 2006) strongly promote aggregation and may also accrue with age.…”

Section: Introductionmentioning

confidence: 99%

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Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…During ageing in C. elegans, various proteins tend to aggregate, including proteasomal and ribosomal proteins, and chaperones HSP70 and HSP90 (REF. 57). Moreover, many of these ageing related aggregation prone proteins are included in amyloid plaques, as observed in Alzheimer, Parkinson, and Huntington diseases and in aggregates in amyotrophic lateral sclerosis 57 .…”

Section: Derailment During Normal Ageingmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

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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