Protein Homeostasis and Ageing in C. elegans

Alavez, Silvestre

doi:10.1007/978-3-319-44703-2_12

Cited by 3 publications

(5 citation statements)

References 97 publications

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“…C. elegans displays a loss of protein homeostasis during ageing, hallmarked by a global accumulation of insoluble, aggregated proteins (David et al, 2010;Walther et al, 2015). Protein aggregation can be used as a proxy to investigate the state of protein homeostasis in animals (Alavez, 2017), and aggregated proteins can be isolated through detergent fractionation (David et al, 2010;Groh et al, 2017;Huang et al, 2019;Walther et al, 2015). In our study, we used a 1% SDS fractionation method to extract an insoluble protein fraction from animals (Supplemental Figure 1A, B), which we from here on refer to as aggregated proteins.…”

Section: Silencing Of Distinct Ddr Components Exacerbates Endogenous Protein Aggregationmentioning

confidence: 99%

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Huiting

Duque‐Jaramillo

Seinstra

et al. 2021

Preprint

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To maintain genome integrity, cells rely on a complex system of DNA repair pathways and cell cycle checkpoints, together referred to as the DNA damage response (DDR). Impairments in DDR pathways are linked to cancer, but also to a wide range of degenerative processes, frequently including progressive neuropathy and accelerated aging. How defects in mechanistically distinct DDR pathways can drive similar degenerative phenotypes is not understood. Here we show that defects in various DDR components are linked to a loss of protein homeostasis in Caenorhabditis elegans. Prolonged silencing of atm-1, brc-1 or ung-1, central components in respectively checkpoint signaling, double strand break repair and base excision repair enhances the global aggregation of proteins occurring in adult animals, and accelerates polyglutamine protein aggregation in a model for neurodegenerative diseases. Overexpression of the molecular chaperone HSP-16.2 prevents enhanced protein aggregation in atm-1, brc-1 or ung-1-compromised animals. Strikingly, rebalancing protein homeostasis with HSP-16.2 almost completely rescues age-associated impaired motor function in these animals as well. This reveals that the consequences of a loss of atm-1, brc-1 or ung-1 converge on an impaired protein homeostasis to cause degeneration. These findings indicate that a loss of protein homeostasis is a crucial downstream consequence of DNA repair defects, and thereby provide an attractive novel framework for understanding the broad link between DDR defects and degenerative processes.

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Section: Silencing Of Distinct Ddr Components Exacerbates Endogenous Protein Aggregationmentioning

confidence: 99%

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Huiting

Duque‐Jaramillo

Seinstra

et al. 2021

Preprint

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“…This is orchestrated by several post-translational mechanisms through the aid of protein chaperones, co-chaperones and mediators that fold and/or refold misfolded proteins, maintaining the correct conformation and/or attempting to sequester or degrade toxic soluble misfolded species via aggresomes and autophagy. It has been suggested that cells actively sequester misfolded proteins in chaperone-rich quinary (Q-body) compartments (Alavez, 2017;Escusa-Toret et al, 2013;Roth and Balch, 2013). These misfolded species are then directed to the ubiquitin proteasome system (UPS) and/or the autophagy lysosome pathway (ALP) for degradation so as to prevent neurotoxicity (Manecka et al, 2017).…”

mentioning

confidence: 99%

SUMOylation, aging and autophagy in neurodegeneration

Vijayakumaran

Pountney

2018

NeuroToxicology

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Protein homeostasis is essential for the wellbeing of several cellular systems. Post-translational modifications (PTM) coordinate various pathways in response to abnormal aggregation of proteins in neurodegenerative disease states. In the presence of accumulating misfolded proteins and toxic aggregates, the small ubiquitin-like modifier (SUMO) is associated with various substrates, including chaperones and other recruited factors, for refolding and for clearance via proteolytic systems, such as the ubiquitin-proteasome pathway (UPS), chaperone-mediated autophagy (CMA) and macroautophagy. However, these pathological aggregates are also known to inhibit both the UPS and CMA, further creating a toxic burden on cells. This review suggests that re-routing cytotoxic aggregates towards selective macroautophagy by modulating the SUMO pathway could provide new mechanisms towards neuroprotection.

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“…For example, a common feature of aging in numerous species, including C. elegans, is the accumulation of a particular kind of protein aggregates, called lipofuscin, composed by fluorescent pigments, oxidized proteins, lipids, carbohydrates, and metals (Porta, 2002). Also, numerous degenerative diseases including Alzheimer's disease and Parkinson's disease are partly caused by the aggregation and deposition of aberrant forms of particular proteins causing neuronal damage (Soto, 2003;Alavez, 2017).…”

Section: Ii3 Loss Of Proteostasis As An Aging Promotermentioning

confidence: 99%

“…This event causes a time-dependent loss of protein quality control contributing to protein aggregate formation. Moreover, there is evidence that an increased expression of HSPs in numerous organisms including C. elegans and Drosophila melanogaster increase individuals lifespan (Murshid et al, 2013;Alavez, 2017).…”

Section: Ii31 the Stress Responsementioning

confidence: 99%

“…Proteins that need to be removed from the cells are normally processed by the degradation system UPS. Damaged or obsolete proteins are covalently marked with several ubiquitin proteins so they can be degraded by an ATPdependent process in the proteasome (Alavez, 2017). The UPS is how the cells degrade most of their cytosolic and nuclear proteins as well as aberrant proteins (Bustamante et al, 2018).…”

Section: Ii32 the Degradation System: Ubiquitin/proteasome (Ups)mentioning

confidence: 99%

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Calcium signaling modulators: a novel pharmacological intervention to delay aging in Caenorhabditis elegans

Casas¹

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§ g-CD: gamma-cyclodextrin § [Ca 2+ ]cyt: cytosolic Ca 2+ concentration § [Ca 2+ ]ER: endoplasmic reticulum Ca 2+ concentration § 2,5-BHQ: 2,5-di-tert-butylhidroquinone § 2,6-BHQ: 2,6-di-tert-butylhidroquinone § ACh: acetylcholine § AMPK: adenosine monophosphate-activated protein kinase § ATF-4: activating transcription factor-4 § ATF-6: activating transcription factor-6 § ATG: autophagy related proteins § BLPS: body lengths per second § CaMKKb:elegans nicotinic acetylcholine receptor § EPG: electropharyngeogram § EPSP: excitatory post-synaptic potential § ER: endoplasmic reticulum § ETC: electron transport chain § FRET: fluorescence resonance-energy transfer § FuDR: 5-fluoro-2'-deoxyuridine § GFP: green fluorescent protein § HS: heat Shock § HSF: heat shock transcriptional factors § HSPs: heat shock proteins § HVA: high voltage activated current § I1-I5: pharyngeal interneurons § IGF-1: insulin-like growth factor 1 § IIS: insulin/Insulin-like growth factor signaling pathway § ILPs: insulin-like peptide ligands § IPSPs: small notch hyperpolarizations § IRE-1: inositol-requiring-kinase-1 ABBREVIATIONS § LKB1: serine/threonine kinase 11 § M1-M5: pharyngeal motroneurons § MAMs: Mitochondria-ER Associated Membranes § mc: pharyngeal marginal cells § MCs: pharyngeal MC neurons § mTOR: mechanistic target of rapamycin § NMJ: neuromuscular junction § NSMs: neurosecretory-motor neurons § O/N: overnight § OP50: E. coli bacterial strain § PAS: Phagophore assembly site § PERK: protein kinase RNA-like endoplasmic reticulum kinase § pm1-pm8: pharyngeal muscular segments § RNAi: RNA of interference § ROS: Radical oxygen species § SIRTs: sirtuins: silent information regulator proteins. § TAK1: transforming growth factor-b-activated kinase 1 § Tg: thapsigargin § UPS: Ubiquitin/Proteasome system § VDCC: voltage dependent Ca 2+ channels § WHO: World Health Organization § XBP-1: X-box binding protein 1 C. elegans STRAINS AQ2038 pmyo2::YC2.1 Cameleon YC2.1 Cytosolic Ca 2+ probe Lifespan Ca 2+ dynamics -AQ2121 pmyo3::YC2.1 Cameleon YC2.1 Cytosolic Ca 2+ probe Ca 2+ dynamics Motility assay -AQ3055 pmyo-2::2mt8::YC3.60 Cameleon YC3.6 Mitochondrial Ca 2+ probe Ca 2+ dynamics -

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Protein Homeostasis and Ageing in C. elegans

Cited by 3 publications

References 97 publications

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

Preserving protein homeostasis prevents motor impairment in DNA Damage Response-compromised C. elegans

SUMOylation, aging and autophagy in neurodegeneration

Calcium signaling modulators: a novel pharmacological intervention to delay aging in Caenorhabditis elegans

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