Adapting Proteostasis for Disease Intervention

Balch, William E.; Morimoto, Richard I.; Dillin, Andrew; Kelly, Jeffery W.

doi:10.1126/science.1141448

Cited by 2,173 publications

(2,121 citation statements)

References 39 publications

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“…The likelihood of developing diseases of protein dysfunction, such as neurodegenerative disorders, is increased upon aging, due in part to the decline of the HSR during the aging process (Ben‐Zvi, Miller, & Morimoto, 2009; Labbadia & Morimoto, 2015). Activators of the HSR have been suggested as possible therapeutic strategies for diseases of aging (Balch, Morimoto, Dillin, & Kelly, 2008; Calamini & Morimoto, 2012; Neef, Turski, & Thiele, 2010; Westerheide & Morimoto, 2005), but many of the small molecules known to modulate HSF1 activity have cytotoxicity and poor bioavailability. Our data suggest that modulating SIR‐2.1 activity may prevent an age‐associated decline in the HSR and may prevent polyglutamine aggregation in a C. elegans Huntington's disease model.…”

Section: Discussionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat‐shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA‐bound state of HSF1 through deacetylation of the DNA‐binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell‐cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF‐1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR‐1. This negative regulation requires the SIRT1 homolog SIR‐2.1. In addition, knockdown of CCAR‐1 via ccar‐1 RNAi works through SIR‐2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.

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Section: Discussionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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“…This has revealed changed expression of several genes involved in many cellular pathways, including members of HSP families. Instead of looking at physiologically induced aging effects on gene expression, we tried to determine whether individual molecular functions of small HSPs, respectively HSP70‐dependent assistance of (re)folding reactions (CG14207) or HSP70‐independent prevention of polyQ aggregation (HSP67BC), can contribute to an enhanced lifespan in line with the theory that overall protein homeostasis is important for healthy aging (Balch et al ., 2008) and that a multitude of molecular chaperones of which the expression is regulated via HSF‐1, a transcriptional regulator of stress‐inducible gene expression, are vital in both the protection against protein folding diseases and aging (Walker et al ., 2001; Morley & Morimoto, 2004; Cohen et al ., 2006). In line, previous data had already demonstrated that the HSP22, the mitochondrial D. melanogaster small HSP family member, can induce longevity (Morrow et al ., 2004).…”

Section: Discussionmentioning

confidence: 99%

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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“…Proteostasis involves balanced cellular production and folding of proteins, as well as clearance of old, misfolded, and damaged proteins 5,10 . The cardiac PQC network gener ates and conserves functional pro teins, and counter acts the proteotoxic stress resulting from damaged proteins.…”

Section: The Proteostasis Network Componentsmentioning

confidence: 99%

“…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 .…”

mentioning

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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Adapting Proteostasis for Disease Intervention

Cited by 2,173 publications

References 39 publications

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

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

Proteostasis in cardiac health and disease

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