Proteostasis & Protein Misfoldment Mechanisms

Amolydosis, misfolded proteins, is what many centenurian and super centenarians die from the most. We therefore need ot better understand this mechanism is we want to achieve our optimal designed healthy Life-span of at least 120 years of age. In this Page, Mechanisms of proteostasis will first be examined (Section A). Thereafter, we will look at different diseases and accelerated aging that results from proteostasis and protein misfoldment disorders (Section B)

Section A.

Mechanisms of Action

Introduction

Proteostasis is the process by which biological pathways within cells control the biogenesis, (birth) folding, trafficking and degradation of proteins. (1,2). The notion of proteostasis maintenance is central to understanding the cause of accelerated aging and chronic diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes (3) as well as aggregation-associated degenerative disorders. (4)  With regard to optimal longevity, cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostasis perturbations by pathogens such as viruses. (2)  

According to the status of the research we have seen, the main mechanisms by which proteostasis occurs include regulated protein translation, chaperone assisted protein folding and protein degradation pathways. Adjusting each of these mechanisms to the demand for proteins is essential to maintain all cellular functions relying on a correctly folded proteome.

TEXT UNDER CONSTRUCTION

The ribosome’s Raison D’être In proteostasis

The starting point in the proteostasis process is during translation or what can also be called genetic expression. (*) This is accomplished thanks to the ribosome, which is an organel inside the cell. The ribosome is key insofar as protein folding is concerned. Codons can modulate the process. (5)

Molecular chaperones and post-translational maintenance in proteostasis

In order to maintain protein homeostasis post-translationally, the cell makes use of molecular chaperones, including chaperonins, which help in the assembly or disassembly of proteins. (6)  Chaperones begin to assist in protein folding as soon as a nascent peptide chain longer than 60 amino acids emerges from the ribosome exit channel. (8) One of the most studied ribosome binding chaperones is trigger factor. Trigger Factor works to stabilize the peptide, promotes its folding, prevents aggregation, and promotes refolding of denatured model substrates.. (9) Trigger factor not only directly works to properly fold the protein but also recruits other chaperones to the ribosome, such as Hsp70, which is a heat shock protein. Hsp70 surrounds an unfolded peptide chain, thereby preventing aggregation and promoting folding (7, 8).

Regulating proteostasis by protein degradation

The third component of the proteostasis network is the protein degradation machinery. Protein degradation occurs in proteostasis when the cellular signals indicate the need to decrease overall cellular protein levels. The effects of protein degradation can be local, with the cell only experiencing effects from the loss of the degraded protein itself or widespread, with the entire protein landscape changing due to loss of other proteins’ interactions with the degraded protein. (6)

Multiple substrates are targets for proteostatic degradation. These degradable substrates include nonfunctional protein fragments produced from ribosomal stalling during translation, misfolded or unfolded proteins, aggregated proteins, and proteins that are no longer needed to carry out cellular function. Several different pathways exist for carrying out these degradation processes. When proteins are determined to be unfolded or misfolded, they are typically degraded via the unfolded protein response (UPR) or endoplasmic-reticulum-associated protein degradation (ERAD). Autophagy, or self engulfment, lysosomal targeting, and phagocytosis (engulfment of waste products by other cells) can also be used as proteostatic degradation mechanisms (6)

Signaling events in proteostasis

Protein misfolding is detected by mechanisms that are specific for the cellular compartment in which they occur. Distinct surveillance mechanisms that respond unfolded protein have been characterized in the cytoplasm, ER and mitochondria. This response acts locally in a cell autonomous fashion but can also extend to intercellular signaling to protect the organism from anticipated proteotoxic stress.

Cell-autonomous stress responses

Cellular stress response pathways detect and alleviate proteotoxic stress which is triggered by imbalances in proteostasis. The cell-autonomous regulation occurs through direct detection of misfolded proteins or inhibition of pathway activation by sequestering activating components in response to heat shock. Cellular responses to this stress signaling include transcriptional activation of chaperone expression, increased efficiency in protein trafficking and protein degradation and translational reduction.

Work on the model organism C. elegans has shown that neurons play a role in this intercellular communication of cytosolic HSR. Stress induced in the neurons of the worm can in the long run protect other tissues such as muscle and intestinal cells from chronic proteotoxicity. Similarly ER and mitochondrial UPR in neurons are relayed to intestinal cells . These systemic responses have been implicated in mediating not only systemic proteostasis but also influence organismal aging.[11]

Section B

Proteostasis and diseases of protein folding

Dysfunction in proteostasis can arise from errors in or misregulation of protein folding. The classic examples are missense mutations and deletions that change the thermodynamic and kinetic parameters for the protein folding process.[1] These mutations are often inherited and range in phenotypic severity from having no noticeable effect to embryonic lethality. Disease develops when these mutations render a protein significantly more susceptible to misfolding, aggregation, and degradation. If these effects only alter the mutated protein, the negative consequences will only be local loss of function. However, if these mutations occur in a chaperone or a protein that interacts with many other proteins, dramatic global alterations in the proteostasis boundary will occur. Examples of diseases resulting from proteostatic changes from errors in protein folding include cystic fibrosis, Huntington’s disease, Alzheimer’s disease, lysosomal storage disorders, and others.[12]

Proteostasis and cancer

The unregulated cell division that marks cancer development requires increased protein synthesis for cancer cell function and survival. This increased protein synthesis is typically seen in proteins that modulate cell metabolism and growth processes. Cancer cells are sometimes susceptible to drugs that inhibit chaperones and disrupt proteostasis, such as Hsp90 inhibitors or proteasome inhibitors.[1] Furthermore, cancer cells tend to produce misfolded proteins, which are removed mainly by proteolysis.[14] Inhibitors of proteolysis allow accumulation of both misfolded protein aggregates, as well as apoptosis signaling proteins in cancer cells.[15][16] This can can change the sensitivity of cancer cells to antineoplastic drugs; cancer cells either die at a lower drug concentration, or survive, depending on the type of proteins that accumulate, and the function these proteins have.[17] Proteasome inhibitor bortezomib was the first drug of this type to receive approval for treatment of multiple myeloma.[18]

Proteostasis and obesity

A hallmark of cellular proteostatic networks is their ability to adapt to stress via protein regulation. Metabolic disease, such as that associated with obesity, alters the ability of cellular proteostasis networks adapt to stress, often with detrimental health effects. For example, when insulin production exceeds the cell’s insulin secretion capacity, proteostatic collapse occurs and chaperone production is severely impaired. This disruption leads to the disease symptoms exhibited in individuals with diabetes.[1]

Proteostasis and accelerated aging

Over time, the proteostasis network becomes burdened with proteins modified by reactive oxygen species and metabolites that induce oxidative damage.[1] These byproducts can react with cellular proteins to cause misfolding and aggregation (especially in nondividing cells like neurons). This risk is particularly high for intrinsically disordered proteins. The IGFR-1 pathway has been shown in C. elegans to protect against these harmful aggregates, and some experimental work has suggested that upregulation of insulin growth factor receptor 1 (IGFR-1) may stabilize proteostatic network and prevent detrimental effects of aging.[1] Expression of the chaperome, the ensemble of chaperones and co-chaperones that interact in a complex network of molecular folding machines to regulate proteome function, is dramatically repressed in human aging brains and in the brains of patients with neurodegenerative diseases. Functional assays in C. elegans and human cells have identified a conserved chaperome sub-network of 16 chaperone genes, corresponding to 28 human orthologs as a proteostasis safeguard in aging and age-onset neurodegenerative disease. [19]

Tentative Conclusion

So now the question is  how to upregulate the heat shock response so that the body’s proteins don’t get overly damaged in terms of degradation during times of cellular stress. Contrarily to Conventional Medicine,  In Holistic & Happiness Medicine, we have a few holistic techniques that will activate the HS proteins, their genes while optimizing longevity and helping to reverse chronic diseases.

 

Reference and Precision Notes

1A portmanteau of the words protein and homeostasis, is Powers, E.T.; Morimoto, R.I.; Dillin, A.; Kelly, J.W.; Balch, W.E. (2009). “Biological and Chemical Approaches to Diseases of Proteostasis Deficiency”. Annu. Rev. Biochem. 78: 959–91. doi:10.1146/annurev.biochem.052308.114844. PMID 19298183.

2.  Balch WE, Morimoto RI, Dillin A, Kelly JW (Feb 2008). “Adapting proteostasis for disease intervention”. Science. 319: 916–919. doi:10.1126/science.1141448. PMID 18276881.

Mu, T-W.; Ong, D.S.T.; Wang, Y-J; Balch, W. E.; Yates, J.R.; Segatori, L.; Kelly, J.W. (2008). “Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases”. Cell. 134: 769–781. doi:10.1016/j.cell.2008.06.037. PMC 2650088pastedGraphic.png. PMID 18775310.

4 Cohen, E., Paulsson, J. F., Blinder, P., Burstyn-Cohen, T., Du, D., Estepa, G., Adame, A., Pham, H. M., Holzenberger, M., Kelly, J. W., Masliah, E. & Dillin, A. (2009). “Reduced IGF-1 signaling delays age-associated proteotoxicity in mice”. Cell. 139: 1157–69. doi:10.1016/j.cell.2009.11.014.

5 Cavagnero, S. & Fedyukina, D. V. (March 2011). “Protein Folding at the Exit Tunnel”. Annual Review of Biophysics. 40: 337–359. doi:10.1146/annurev-biophys-042910-155338. PMID 21370971.

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a b c Bustamante, C. J., et.al. (2014). “Mechanisms of Cellular Proteostasis: Insights from Single-Molecule Approaches”. Annual Review of Biophysics. 43: 119–140.

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a b c Ye, K., et.al. (2013). “Molecular Chaperone Functions in Protein Folding and Proteostasis”. Annual Review of Biophysics. 82: 323–355. doi:10.1146/annurev-biochem-060208-092442. PMID 23746257.

8  Vabulas, M. R. et. al. (2010). “Protein Folding in the Cytoplasm and the Heat Shock Response”. Cold Spring Harb Perspect Biology. 2: 1–18.

Hoffman, A. (June 2010). “Structure and function of the molecular chaperone Trigger Factor”. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 1803: 650–661. doi:10.1016/j.bbamcr.2010.01.017. PMID 20132842.

10 Yébenes, H., et. al. (Aug 2011). “Chaperonins: two rings for folding”. Trends Biochem Sci. 36: 424–432. doi:10.1016/j.tibs.2011.05.003. PMID 21723731.

11  Taylor RC, et al. (2014). “Systemic stress signalling: understanding the cell non-autonomous control of proteostasis”. Nature Reviews Molecular Cell Biology. 15: 506–14. doi:10.1038/nrm3752. PMID 24556842.

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Hipp MS, et al. (2014). “Proteostasis impairment in protein-misfolding and aggregation diseases”. Trends Cell Biol. 24: 211–217. doi:10.1016/j.tcb.2014.05.003. PMID 24946960.

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Brehme M, Voisine C (2016). “Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity”. Dis Model Mech. 9: 823–838. doi:10.1242/dmm.024703. PMC 5007983pastedGraphic.png. PMID 27491084.

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Cohen-Kaplan V, Livneh I, Avni N, Cohen-Rosenzweig C, Ciechanover A. “The ubiquitin-proteasome system and autophagy: Coordinated and independent activities”. Int J Biochem Cell Biol. 79: 403–418. doi:10.1016/j.biocel.2016.07.019. PMID 27448843.

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Moschovi M, Critselis E, Cen O, Adamaki M, Lambrou GI, Chrousos GP, Vlahopoulos S (2015). “Drugs acting on homeostasis: challenging cancer cell adaptation”. Expert Rev Anticancer Ther. 15: 1405–17. doi:10.1586/14737140.2015.1095095. PMID 26523494.

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Sionov RV, Vlahopoulos SA, Granot Z. “Regulation of Bim in Health and Disease”. Oncotarget. 6: 23058–134. doi:10.18632/oncotarget.5492. PMC 4695108pastedGraphic.png. PMID 26405162.

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Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA (April 2012). “Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators”. Mol. Cell. Endocrinol. 351: 142–51. doi:10.1016/j.mce.2012.01.003. PMID 22273806.

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Adams J. “Proteasome inhibition in cancer: development of PS-341”. Semin Oncol. 28: 613–9. doi:10.1016/s0093-7754(01)90034-x. PMID 11740819.

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Brehme M, et al. (2014). “A conserved chaperome sub-network safeguards protein homeostasis in aging and neurodegenerative disease”. Cell Rep. 9: 1135–1150. doi:10.1016/j.celrep.2014.09.042. PMC 4255334pastedGraphic.png. PMID 25437566.

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Bulawa C.E., Connelly S., DeVit M., Wang L. Weigel, Fleming J. Packman, Powers E.T., Wiseman R.L., Foss T.R., Wilson I.A., Kelly J.W., Labaudiniere R. (2012). “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade”. Proc. Natl. Acad. Sci. 109: 9629–9634. doi:10.1073/pnas.1121005109.

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Plate L., Cooley C.B., Chen J.J., Paxman R.J., Gallagher C.M., Madoux F., Genereux J.C., Dobbs W., Garza D., Spicer T.P., Scampavia L., Brown S.J., Rosen H., Powers E.T., Walter P., Hodder P., Wiseman R.L., Kelly J.W. (2016). “Small Molecule Proteostasis Regulators that Reprogram the ER to Reduce Extracellular Protein Aggregation”. eLife. 5: 15550. doi:10.7554/elife.15550.

http://www.enzolifesciences.com/platforms/proteostasis/

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(*). In molecular biology and genetics, translation is the process in which ribosomes in the cytoplasm or ER synthesize proteins after the process transcription of DNA to RNA in the cell’s nucleus. The entire process is called gene expression.In translation, messenger RNA (mRNA) is decoded in a ribosome, outside the nucleus, to produce a specific amino acid chain, or polypeptide. The  later folds into an active protein and performs its functions in the cell. The ribosome facilitates decoding by inducing the binding of complementary tRNA anticodon sequences to mRNA codons. The tRNAs carry specific amino acids that are chained together into a polypeptide as the mRNA passes through and is “read” by the ribosome. Translation proceeds in three phases:

1 Initiation: The ribosome assembles around the target mRNA. The first tRNA is attached at the start codon. 2 Elongation: The tRNA transfers an amino acid to the tRNA corresponding to the next codon. The ribosome then moves (translocates) to the next mRNA codon to continue the process, creating an amino acid chain. 3 Termination: When a stop codon is reached, the ribosome releases the polypeptide.

In prokaryotes (bacteria), translation occurs in the cytoplasm, where the large and small subunits of the ribosome bind to the mRNA. In eukaryotes, translation occurs in the cytosol or across the membrane of the endoplasmic reticulum in a process called co-translational translocation. In co-translational translocation, the entire ribosome/DNA complex binds to the outer membrane of the rough endoplasmic reticulum (ER) and the new protein is synthesized and released into the cytosol; the newly created polypeptide can be stored inside the ER for future vesicle transport and secretion outside the cell, or immediately secreted.

Many types of transcribed RNA, such as transition RNA, ribosomal RNA, and small nuclear RNA, do not undergo translation into proteins. A number of antibiotics act by inhibiting translation. These include anisomycin, cycloheximide, chloramphenicol, tetracycline, streptomycin, erythromycin, and puromycin. Prokaryotic ribosomes have a different structure from that of eukaryotic ribosomes, and thus antibiotics can specifically target bacterial infections without any harm to a eukaryotic host’s cells.

(***) Chaperonins are a special class of chaperones that promote native state folding by cyclically encapsulating the peptide chain.[8] Chaperonins are divided into two groups. Group 1 chaperonins are commonly found in bacteria, chloroplasts, and mitochondria. Group 2 chaperonins are found in both the cytosol of eukaryotic cells as well as in archaea.[10] Group 2 chaperonins also contain an additional helical component which acts as a lid for the cylindrical protein chamber, unlike Group 1 which instead relies on an extra cochaperone to act as a lid. All chaperonins exhibit two states (open and closed), between which they can cycle. This cycling process is important during the folding of an individual polypeptide chain as it helps to avoid undesired interactions as well as to prevent the peptide from entering into kinetically trapped states.[10]

(**) Lysosomal storage diseases are a group of about 50 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective, because of a mutation, the large molecules accumulate within the cell, eventually killing it.[2]

Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar-containing proteins), or so-called mucopolysaccharides. Individually, LSDs occur with incidences of less than 1:100,000; however, as a group, the incidence is about 1:5,000 – 1:10,000.[3][4] Most of these disorders are autosomal recessively inherited such as Niemann–Pick disease, type C, but a few are X-linked recessively inherited, such as Fabry disease and Hunter syndrome (MPS II).

The lysosome is commonly referred to as the cell’s recycling center because it processes unwanted material into substances that the cell can use. Lysosomes break down this unwanted matter by enzymes, highly specialized proteins essential for survival. Lysosomal disorders are usually triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome does not function normally, excess products destined for breakdown and recycling are stored in the cell.

Like other genetic disorders, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic – all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome.

LSDs affect mostly children and they often die at a young and unpredictable age, many within a few months or years of birth. Many other children die of this disease following years of suffering from various symptoms of their particular disorder.

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