The role of protein clearance mechanisms in organismal ageing and age-related diseases

Vı́lchez, David; Sáez, Isabel; Dillin, Andrew

doi:10.1038/ncomms6659

Cited by 550 publications

(430 citation statements)

References 188 publications

(282 reference statements)

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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%

“…If (re)folding is not an option, chaperones keep the misfolded proteins in a soluble state so that protein degradation systems can dispose of the misfolded substrate. UPS mediated proteolysis is the primary degradation system that removes soluble (chaperone presented), ubiquitylated proteins that are misfolded, oxidized, mutant, or other wise damaged 10,40 (FIG. 1).…”

Section: The Proteostasis Network Componentsmentioning

confidence: 99%

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Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

132

111

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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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Section: The Proteostasis Network Componentsmentioning

confidence: 99%

Section: The Proteostasis Network Componentsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

132

111

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“…A delicately regulated surveillance of protein turnover is especially crucial in postmitotic cells such as neurons and myocytes 230, 231, 232, 233, 234. Eukaryotic cells employ two predominant molecular systems to keep a tight balance between translation and degradation of cellular proteins, namely the proteasomal system and autophagy 235, 236, 237. Dysfunction in either of these two proteolytic systems, and subsequent imbalance of protein homeostasis, is one of nine defining characteristics of cellular aging 238.…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

“…Dysfunction in either of these two proteolytic systems, and subsequent imbalance of protein homeostasis, is one of nine defining characteristics of cellular aging 238. However, severity, time of onset, and acceleration of these pathomechanisms determine to which degree these changes will meet the pathological spectrum 235, 237, 238…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

“…The proteasomal system is tightly controlled by regulatory molecules and executes ubiquitin‐dependent and ‐independent proteolytic degradation 240. Polyubiquitination‐independent recognition and subsequent degradation of oxidized substrates by the core particle 20S proteasome is especially relevant in the context of aging cells 235, 241…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

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Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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Touch and go: nuclear proteolysis in the regulation of metabolic genes and cancer

Maneix

Catic

2016

FEBS Letters

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The recruitment of transcription factors to promoters and enhancers is a critical step in gene regulation. Many of these proteins are quickly removed from DNA after they completed their function. Metabolic genes in particular are dynamically regulated and continuously adjusted to cellular requirements. Transcription factors controlling metabolism are therefore under constant surveillance by the ubiquitin-proteasome system, which can degrade DNA-bound proteins in a site-specific manner. Several of these metabolic transcription factors are critical to cancer cells, as they promote uncontrolled growth and proliferation. This review highlights recent findings in the emerging field of nuclear proteolysis and outlines novel paradigms for cancer treatment, with an emphasis on multiple myeloma.

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The role of protein clearance mechanisms in organismal ageing and age-related diseases

Cited by 550 publications

References 188 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Immune and myodegenerative pathomechanisms in inclusion body myositis

Touch and go: nuclear proteolysis in the regulation of metabolic genes and cancer

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