Review Volume 10, Issue 5 pp 868—901
Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging
- 1 National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens 11635 , Greece
- 2 Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens 15701, Greece
- 3 Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Gediminas Technical University, Vilnius 2040, Lithuania
- 4 Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, Poland
- 5 Department of Analytical Biochemistry, Faculty of Biology and Agriculture, University of Rzeszow, Rzeszow 35-601, Poland
received: April 9, 2018 ; accepted: May 8, 2018 ; published: May 17, 2018 ;https://doi.org/10.18632/aging.101450
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Copyright: Gonos et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Non-enzymatic protein modifications occur inevitably in all living systems. Products of such modifications accumulate during aging of cells and organisms and may contribute to their age-related functional deterioration. This review presents the formation of irreversible protein modifications such as carbonylation, nitration and chlorination, modifications by 4-hydroxynonenal, removal of modified proteins and accumulation of these protein modifications during aging of humans and model organisms, and their enhanced accumulation in age-related brain diseases.
Aging, an inevitable part of the life process, is characterized by a progressive decline in physiological functions that ultimately leads to morbidity and mortality. Aging increases susceptibility to certain class of diseases. Age-related diseases constitute a considerable socioeconomic burden for contemporary societies. As human mean lifespan increases, growing incidence of these diseases has features of a pandemic. The number of people aged 65 or older is projected to grow from an estimated 524 million in 2010 to almost 1.5 billion in 2050, mostly in underdeveloped and developing countries . These trends have obvious serious social and economic implications, such as healthcare costs .
Despite extensive studies, the molecular basis of physiological aging is still poorly understood. Reactive oxygen species (ROS), reactive nitrogen species (RNS) as well as reactive halogen species (RXS) species are believed to play a key role in the aging process. They are generated during aerobic metabolism in living organisms. The term “reactive oxygen species” includes both free radicals [molecules having an odd electron, like superoxide radical anion (O2•-) and hydroxyl radical (HO•)] and species that are not free radicals, like hydrogen peroxide (H2O2), singlet oxygen (1O2) and ozone (O3). The primary source of RNS is usually the nitric oxide radical (•NO). In consequence of ROS and RNS reactions, peroxynitrite ONOO-, anion of peroxynitrous acid ONOOH, may be formed via the near diffusion-limited reaction of •NO and O2•-. The term “reactive nitrogen species” includes also nitrous acid (HNO2), dinitrogen trioxide (N2O3), nitrosyl anion (NO-), nitrosyl cation (NO+), nitrogen dioxide radical (NO2), peroxynitrate (ONOOO-), peroxynitric acid (ONOOOH), nitryl chloride (NO2Cl), and nitronium cation (NO2+) [3,4]. "Reactive halogen species" include HOCl, HOBr, HOI, chlorine, bromine, iodine etc. Hypohalogenous acids (HOX; X = F, Cl, Br, or I) are formed in the body mainly by oxidation of halogen ions by myeloperoxidase. The imbalance between ROS, RNS and RXS production and the antioxidant defense, in favor of prooxidants, is causes oxidative, nitr(os)ative and halogenative stress (OS, NS, XS), respectively. Although at physiological concentrations ROS, RNS and RXS can function as signaling molecules regulating cell proliferation, growth, differentiation and apoptosis [5,6] they react with and damage all classes of endogenous macromolecules including proteins, nucleic acids, lipids and carbohydrates . Proteins are the main targets for such modifications as they are the most abundant cell components in the terms of mass content. The level of protein damage increases under stress conditions and can be in principle an integrative measure of the exposure to OS, NS and XS. However, protein turnover complicates this issue, the more that modified proteins in most cases are subject to preferential degradation ; see Chapter “Removal of modified proteins”.
Protein modifications produced by ROS, RNS and RXS can be classified as transient, reversible or irreversible. Reactions of free radicals with proteins leads to formation of protein radicals, which are generally short-lived, transient and are not useful as biomarkers. Protein hydroperoxides formed upon reactions with ROS are also unstable and decompose forming more stable products [9,10]. Examples of reversible modifications are cysteine (Cys) thiol oxidation to sulfenic acid, methionine (Met) oxidation to methionine sulfoxide or cysteine S-nitrosylation and S-glutathionylation (Table 1, Fig. 1). While these modifications are of vital importance for regulation of protein function and metabolic processes, they are of less importance as permanent markers of OS/NS/XS, so this review will concentrate on irreversible protein modifications.
Table 1. Most important oxidative, nitrative and chlorinative modifications of proteins. After  modified.
|Cysteine||Oxidation of –SH to sulfenic acid (-SOH), sulfinic acid (-SO2H) or sulfonic acid (-SO3H)|
Formation of a disulfide bond –SS-
|First stage, and in some cases second stage reversible|
|Cysteine||Nitrosylation [formation of (-SNO)]||Reversible|
|Tyrosine, tryptophan, other amino acids||Protein radicals||May be reduced or react to form further products|
|Glutamic acid, tyrosine, lysine, leucine, valine, proline, isoleucine||Hydroperoxides||May be reduced; decompose to further products|
|Lysine, arginine, proline, threonine||Formation of carbonyl derivatives by direct oxidative attack on amino-acid side chains (α-aminoadipic semialdehyde from lysine, glutamic semialdehyde from arginine, 2-pyrrolidone from proline, and 2-amino-3- ketobutyric acid from threonine)||Decarbonylation [?]|
|Lysine, cysteine, histidine||Formation of carbonyl derivatives by secondary reaction with reactive carbonyl compounds derived from oxidation of carbohydrates (glycoxidation products), lipids (MDA, 4-HNE, ACR) and advanced glycoxidation and lipoxidation end products||Irreversible|
|Methionine||Methionine sulfoxide||Reversible by methionine sulfoxide reductases|
|Tyrosine||Hydroxylation to 3,4-dihydroxyphenylalanine|
Dimerization to dityrosine
|Tyrosine, tryptophan, histidine||Nitration [introduction of (-NO2)]||Irreversible [Denitration ?]|
|Tyrosine||Chlorination to 3-chlorotyrosine||Irreversible|
|Tryptophan||5-Hydroxytryptophan, 7-hydroxytryptophan, kynurenine, N-formylkynurenine||Irreversible|
Figure 1. Selected non-enzymatic protein modifications. (A) oxidation of cysteine residues in proteins. Cysteine residues may be oxidized to sulfenic, sulfinic and sulfonic derivatives or form disulfide bonds. Oxidation to sulfenic acid and formation of disulfides is reversible; (B) modifications of cysteine residues in proteins: formation of nitrosocysteine and S-glutathionylation; (C) oxidation of methionine forms methionine sulfoxide, which may be reduced back to methionine by methionine sulfoxide reductases (MSR); (D) formation of hydroperoxides of valine, lysine and leucine; (E) formation of carbonyl derivatives of lysine, arginine, His and threonine; (F) formation of 4-hydroxynonenal adducts of cysteine, His and lysine; (G) oxidative modifications of phenylalanine; (H) modifications of tyrosine; (I) modifications of tryptophan.
FORMATION OF NON-ENZYMATICALLY MODIFIED PROTEINS
Compared to other oxidative modifications, carbonyls are relatively difficult to induce and in contrast to, for example, methionine sulfoxide and cysteine disulfide bond formation, carbonylation is an irreversible oxidative process . Protein carbonylation is an oxidative modification induced by ROS, RNS, RXS and reactive aldehydes. It consists in formation of reactive aldehyde or ketone residues on proteins, which can react with 2,4-dinitrophenylhydrazine (DNPH) forming hydrazones. There are two ways of protein carbonylation. "Primary protein carbonylation" is due to oxidation of some amino acid residues, initiated by ROS, RNS and RXS, often catalyzed by metals while “secondary protein carbonylation” is caused by addition of aldehydes. The aldehydes are formed mainly in the process of lipid peroxidation [malondialdehyde, MDA; 4-hydroxy-2,3-trans-nonenal, (4-HNE); 2-propenal (acrolein, ACR)], but may be also by-products of glycolysis and the glycation process (methylglyoxal, glyoxal).
In the first pathway, ROS, RNS and RXS directly attack the protein producing, eventually, highly reactive carbonyl derivatives by oxidation of the side chains of lysine (Lys), arginine (Arg), proline (Pro), and threonine (Thr) residues, particularly via metal-catalysed oxidation, from the cleavage of peptide bonds in the α-amidation pathway or by oxidation of glutamyl residues. The main carbonyl products of metal-catalysed protein oxidation are glutamic semialdehyde, a product of oxidation of Arg, aminoadipic semialdehyde, a product of Lys oxidation, 2-pyrrolidine, a product of histidine (His) oxidation and 2-amino-3-ketobutyric acid, a product of oxidation of Thr (Fig. 1E) . Carbonylation is site-specific; an iterative statistical method has been proposed to identify potential sites of carbonylation .
The second type of reaction involves the addition of reactive aldehyde groups to the side chains of Cys, His, or Lys residues via Michael addition (Fig. 1F). Reactive carbonyl groups can be also generated through the reaction of the amino group of lysine residues with reducing sugars or their oxidation products (glycation/glycoxidation products) .
Dimerization of tyrosyl radicals (Tyr•) leads to the formation of dityrosine (Fig. 1H). Products of oxidative destruction of tryptophan (Try) include kynurenine and N-formylkynurenine (Fig. 1I). All these products have their characteristic fluorescence and their content can be easily evaluated fluorimetrically [15,16].
RNS can oxidize proteins and alter their biological functions also in other ways. Nitration of amino acids, such as tyrosine (Tyr) and, to a lesser extent, Try and His, is an important form of protein modification that occurs during NS . Tyr, a nonessential aromatic amino acid, carrying a hydroxyl group, is often exposed at the surface of proteins, making them vulnerable to nitration, as well as oxidation [18,19].
The nitration of Tyr is mediated by RNS such as ONOO-/ONOOH and •NO2 although nitration can also by accomplished by heme peroxidases and nitrite . The two main mechanisms of biological nitration, the ONOO-/ONOOH and the heme peroxidase pathways, lead both to the formation of Tyr• and •NO2, which combine with diffusion controlled rates to form 3-nitrotyrosine (3-NT; Fig. 1H). The oxidants leading to Tyr• formation include CO3•-, •OH or oxo–metal complexes. Importantly, •NO2 alone is inefficient in promoting nitration, because its reaction with Tyr to produce Tyr• is slow compared to other processes that •NO2 undergoes. I. a., reaction with another Tyr• to form 3,3-dityrosine competes with the formation of 3-NT. However, under certain conditions protein radicals can be stabilized, e. g. when intra- and intermolecular dimerization is limited due to diffusional and spatial constraints, both in aqueous and hydrophobic compartments. In such cases reaction of Tyr• with •NO2 may be favoured. Another pathway competing with Tyr nitration is the formation of 3-hydroxytyrosine, which can be performed mainly by •OH or oxo–metal complexes. An alternative radical mechanism for Tyr nitration involves the reaction of a Tyr• with •NO to form 3-nitrosotyrosine followed by two-electron oxidation to 3-NT .
Hypochlorous acid (HOCl) is the main player involved in protein chlorination in vivo . HOCl is generated by the reaction of H2O2 with chloride ions (Cl-) catalysed by myeloperoxidase (MPO, EC 22.214.171.124) [22–24]. For a long time, myeloperoxidase (MPO) was regarded as the only human enzyme known to produce HOCl at the physiological concentrations of chloride (100-140 mM) . Nevertheless, recent findings revealed that another mammalian heme peroxidase, peroxidasin 1, is capable of catalysing the oxidation of chloride to HOCl, too. The enzyme is also known as vascular peroxidase 1 [26–29]. Up to 80% of the H2O2 generated by activated neutrophils may be used to produce local concentrations as high as 20-400 µM HOCl within an hour [30,31]. The pKa of HOCl is 7.59 , so at physiological pH values, HOCl exists in equilibrium with its anion -OCl at approximately equal concentrations. HOCl is a powerful oxidant and plays an important physiological role. MPO-produced HOCl is involved in innate immune response and kills invading pathogens [33,34]. Green et al.  showed that the diminution of HOCl production observed with decreasing Cl- availability results in impaired killing of bacteria. However, during chronic inflammation the excessive production of HOCl leads to the host tissue damage and plays a pathophysiological role in inflammatory diseases . Proteins are major targets for HOCl, and the reactions of this oxidant with proteins result in side-chain modifications (mainly chlorination of Tyr residues, Fig. 1H), cross-linking and backbone fragmentation [37,38].
BRAIN PROTEIN MODIFICATIONS BY 4-HYDROXY-2,3-TRANS-NONENAL IN AGING AND NEURODEGENERATIVE DISEASES
Post-mitotic neurons are notably vulnerable to lipid peroxidation since the brain has high levels of polyunsaturated fatty acids, high levels of redox transition metal ions, high oxygen consumption, relatively low levels of low-molecular weight antioxidants and antioxidant enzymes. Peroxidation of polyunsaturated fatty acids, especially linoleic acid, linolenic acid and arachidonic acid by non-enzymatic processes leads to the formation of aldehydes, among them 4-HNE is present at very low concentration in plasma, in the range of 0.28–0.68 μM under physiologic conditions, but its concentration in cells, where it is produced, may be higher (≤5 μM) . 4-HNE concentration can be increased as much as by 100 times under OS conditions . Esterbauer's group demonstrated that 4-HNE formation from arachidonic acid is greater in the presence of NADPH-dependent microsomal enzymes . 4-HNE possesses three reactive functions: a C2=C3 double bond, a C1=O carbonyl group and a hydroxyl group on C4. These functions make this electrophilic molecule highly reactive toward nucleophilic thiol and amino groups. 4-HNE can enter the reaction of Michael addition to thiol or amino groups, which involves the C3 of the C2=C3 double bond or can form Schiff bases between the C1 carbonyl group and primary amines. The kinetics of the Schiff base formation is slow and reversible, making Michael-adducts predominant adducts of 4-HNE to proteins. 4-HNE reacts mainly His, Cys and Lys residues in proteins [176,177] (Fig. 1F, Fig. 2). The formation of the 4-HNE-protein adducts is a bioactive marker of pathophysiological processes [178–180]. 4-HNE forms Michael adducts with enzyme peptidylprolyl cis/trans-isomerase A1 (Pin1), which catalyzes conversions of phosphoserine and phosphothreonine-proline from cis to trans conformation. These adducts were detected by matrix-assisted laser desorption ionization/time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry at the active site residues His157 and Cys113, with Cys113 being the primary site of 4-HNE modification [181–185]. Protein modifications by 4-HNE impairs glutamate and glucose transport, disrupts Ca2+ homeostasis, damages cholinergic neurons thus impairing visuospatial memory and induces apoptosis in PC12 cells (cell line derived from a pheochromocytoma of the rat adrenal medulla) and cultured rat hippocampal neurons [186–188]. Nam et al. (2014) compared N-methyl-D-aspartate receptor type 1 (NMDAR1) and 4-HNE in the hippocampus of D-galactose (D-gal)-induced and naturally aging models of mice . These authors observed an age-dependent reduction of NMDAR1 and an increase in 4-HNE in the dentate gyrus, CA1 and CA3 regions of the hippocampus via immunohistochemistry and Western blot analyses. In the D-gal-induced chemical aging model they noted similar changes in NMDAR1 and 4-HNE although the degree of reduction/increase in NMDAR1/HNE was not as severe as that in the naturally aged mice.
4-HNE-protein adducts were found to be elevated in brain tissues and body fluids of AD, PD, Huntington disease as well as ALS subjects [190,191]. 4-HNE-His adducts were reactive with Aβ core of sensile plaques and neurofibrillary tangles . Hardas et al. (2013) detected oxidative modification of lipoic acid, a key co-factor for a number of proteins including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, by 4-HNE in AD brain . In another study, 4-HNE-Lys adducts were increased in neurons containing neurofibrillary tangles, but also in pyramidal neurons located in the hippocampal tissue sections in AD . The formation 4-HNE adducts with the neuronal glucose transporter GLUT3 and the mitochondrial ATP synthase α subunit in AD brain leads to reduced glucose utilization and energy production in AD [194,195]. Studies conducted by Sultana et al. suggest that 4-HNE-modification of α-enolase, heme oxygenase 1, Collapsin Response Mediator Protein-2 and ATP synthase subunit α are critical in the progression of AD . These authors hypothesized that 4-HNE modification can be not a random event, but occurs on specific proteins, which, in turn, display altered functions. The formation of 4-HNE adducts with α-enolase could inhibit the conversion of plasminogen to plasmin and the degradation of Aβ. In AD brains, the increase of OS leads also to increases of Nrf2 activity as well as, consequently, increases of heme oxygenase 1 level. Heme oxygenase 1 catalyzes the degradation of heme and represents the rate-limiting enzyme in bilirubin production . Collapsin Response Mediator Protein-2 (dihydropyrimidinase-related protein-2) plays an important role in cytoskeletal organization, axonogenesis, axon outgrowth, membrane trafficking and neuronal polarity . The oxidative modification of Collapsin Response Mediator Protein-2, such as formation adducts with 4-HNE, can play an important role in shortening of axons as well as loss of synapses in AD. ATP synthase subunit α, a part of complex V responsible for mitochondrial-resident ATP synthesis. ATP synthase α might by modified by 4-HNE in AD brain, which causes the reduced activity of ATP synthase and reduced ATP levels in AD brain compared to age-matched controls . According to recent study, klotho gene therapy in senescence-accelerated mouse prone-8 (SAMP8) reduced memory deficits, neuronal loss, synaptic damage and 4-HNE levels, and increased mitochondrial SOD-2 and catalase expression. Additionally, the up-regulation of klotho expression decreased Akt and Forkhead box class O1 (FoxO1) phosphorylation. The role of 4-HNE adducts in ALS progression has been recently reviewed by Zarkovic group . ALS is a progressive neurodegenerative disorder characterized by weakness and spasticity, caused by the loss of lower and of upper motor neurons and by secondary neurogenic amyotrophy of striated muscles. An in vitro study demonstrated that 4-HNE impairs the glutamate and glucose transport and the choline acetyltransferase activity in cultured motor neurons , while human autopsy materials have shown increased levels of 4-HNE, which modifies astrocytic glutamate transporter EAAT2 (excitatory amino acid transporter 2) impairing glutamate transport in ALS. Moreover, 4-HNE is able to target SOD1 in ALS . Kabuta et al. (2015) reported that TDP-43, a major component of ubiquitin-positive inclusions in ALS, is bound by 4-HNE, therefore inducing both proteins into toxic aggregates .
It should be mentioned that 4-HNE has also crucial role in αSyn-induced cytotoxicity and neuro-inflammation . These aldehydes can also promote the formation of αSyn oligomers with defined structural properties. Although, 4-HNE modifies αSyn immediately, primarily the His50 residue, oligomer formation only occurs with prolonged incubation times (> 24 h) and involving fewer cross-linking events. 4-HNE can bind to αSyn at an acidic pH, but these modifications cannot promote oligomerization even with increased incubation times . The current objective of research in the field of contribution of 4-HNE-protein adducts is characterization the interactions of 4-HNE with redox sensitive cell signalling proteins. 4-HNE is involved in aging-related signaling pathways, such as NF-κB, AKT, Nrf2 and mTOR. Other signaling pathways involved in aging, for example related to growth factor signaling EGFR, PDGFR and others are also modified by 4-HNE. Understanding how modulation of activities of these signaling pathways contributes to physiological aging and neurodegenerative diseases may pave the way for new therapeutic strategies.
Assay of 4-HNE-protein adducts
The gold standard in studies of protein modifications by lipid peroxidation products, including 4-HNE, in proteomic studies is mass spectrometry, e. g. matrix-assisted laser desorption ionization/time-of-flight/time-of-flight (MALDI-TOF/TOF), ESI-MS or LC-ESI-CID-MS/MS [204–206]. Antibodies against the His adduct of 4-HNE has allowed for facile detection and quantification of 4-HNE-modified proteins by immunochemical techniques (immunoblotting, immunocytochemistry, immunohistochemistry and immuno-electron microscopy.
Two variants of the 4-HNE-ELISA assay have been developed, both of which are based on the 4-HNE-His monoclonal antibodies. The differences between these two assays concern the analytical protocols and the albumin-HNE standards used, allowing very sensitive determination of low amounts of the 4-HNE-protein adducts (the assay denoted HNE-His ELISA Fine) even below 0.025 nmol 4-HNE-His/mg of protein and the one able to detect higher amounts, above 1.5 nmol 4-HNE-His/ mg of protein (the assay denoted HNE-His ELISA Stress) .
ROLE OF OXITATIVE STRESS IN THE BLOOD BRAIN BARRIER AGING
The blood brain barrier (BBB) separates the brain and blood with a large surface area (between 12 and 18 m2 in the average human adult) [208,209]. The opposing membranes of endothelial cells are connected by tight junctions, which are formed through an intricate network of interacting proteins such as claudins, occludin, junctional adhesion molecules and cytoplasmic proteins . Nitta et al. (2003) demonstrated that claudin-5 is a critical determinant of BBB permeability . In the process of healthy aging an increased “leakage” of BBB may occur, not only due to alteration of thickness of basal lamina, endothelial cells, morphology of pericytes and astrocytes, but also as a result of the changes in expression of transporter proteins at the endothelial cell layer of BBB . Bors et al. (2018) reported that the number of tight junctions decreases, the thickness of basal lamina increases as well as the size of astrocyte endfeet extends with advanced age. These authors also demonstrated that the function of P-glycoprotein 1 (P-gp, ABCB1 Abcb1a/Mdr1a), the most important efflux transporter located on the luminal surface of brain capillary endothelial cells is reduced in old Wistar rats . Reduced BBB expression of P-gp was associated with increased brain parenchymal Aβ40 and Aβ42 levels in aged rats , in agreement with the idea that P-gp is an important efflux transporter to remove Aβ from the CNS . Pan et al. (2018) showed that low density lipoprotein receptor-related protein 1 (LRP-1) expression declines with age, which may contribute to Aβ accumulation . Van Assema et al. (2012) studied in vivo effects of gender and aging on human BBB P-gp function in a large sample size using PET and (R)-[11C]verapamil. These authors reported that decreased BBB P-gp is found with aging; nevertheless, effects of age on BBB P-gp function differ between men and women .
The function of BBB can be impaired by ROS/RNS, and these effects are partly mediated by products of lipid peroxidation . The major secondary lipid peroxidation product, 4-HNE can impair the BBB function via the decrease of GSH . Wang et al. (2012) reported that overexpression of actin-depolymerizing factor (ADF) blocks the oxidized low-density lipoprotein (ox-LDL)-induced disruption of endothelial barrier. Furthermore, siRNA-mediated downregulation of ADF expression aggravated ox-LDL-induced disruption of endothelial barrier and ROS formation. ADF seems to be a key signaling molecule in the regulation of BBB integrity and suggest that ADF might be used as a target to modulate diseases accompanied by ox-LDL-induced BBB compromise . It should be also mentioned that several studies suggest a link between synucleinopathies and the cholesterol metabolite 27-hydroxycholesterol (27-OHC). 27-OHC is the major cholesterol metabolite in the blood that crosses BBB, and its levels can increase following hypercholesterolemia, aging and OS, which are all factors for increased synucleinopathy risk. 27-OHC can increase αSyn levels and causes the inhibition of the proteasomal function and reduction in heat shock protein 70 levels as potential cellular mechanisms involved in regulation of αSyn .
REMOVAL OF MODIFIED PROTEINS
The level of posttranslationally modified proteins is a resultant of the rate of protein modification and rate of removal of modified proteins. Aging, as well as several age-related diseases are associated with a decreased ability to maintain proteostasis . All cells have a number of quality control mechanisms in order to maintain the stability and functionality of their proteome. The proteostasis network includes both protein stabilization mechanisms (major heat shock proteins) and protein degradation systems (proteasome and lysosome) [222–224]. In addition, there are several modulators of proteotoxicity (like MOAG-4), that operate through distinct pathways . All these systems work in concert to restore the structure of denatured proteins or to promote their degradation, thus preventing the accumulation of damaged components and ensuring the continuous renewal of the intracellular polypeptides. Many studies have shown that aging is accompanied by failure of proteostasis , while chronic exposure to denatured or aggregated proteins contributes to the development of age-related neurodegenerative diseases such as AD and PD [221,226].
The proteasome is a fundamental multicatalytic enzyme complex, which facilitates the degradation of normal as well as abnormal, damaged, denatured and redundant cellular proteins. Proteasomes are located in different cellular compartments (cytoplasm, nucleus and endoplasmic reticulum) and represent approximately up to 1% of the total cellular protein content. The central role of the proteasomes is demonstrated by their participation in numerous and diverse cellular functions, including the regulation of transcription factor abundance, cell cycle and cellular differentiation. The main proteasomal complex is the 30S/26S proteasome and is composed by the 20S catalytic "core" and the 19S regulatory "cap" (summarized in ).
The 20S proteasome is a barrel-like structure composed of 28 protein subunits that form a complex of 700 kDa. The two outer rings comprise seven different α subunits, while the interior rings consist of seven β subunits, creating an α1-7/β1-7/β1-7/α1-7 layout. The external α rings control the entry of proteasome’s substrates into the β rings, the site of the proteolytic activity. The α-subunits are additionally responsible for the binding of different factors that regulate the activity and specificity of the catalytic core. Three of the seven β subunits, namely β1, β2 and β5, are proteolytically active, having different substrate specificity. Specifically, β1 has a caspase-like activity (CL or PGPH), β2 a trypsin-like (TL) and β5 a chymotrypsin-like activity (CT-L). The protein hydrolysis occurs after acidic peptide bonds, basic amino acids and hydrophobic amino acids, respectively .
The 19S regulatory complex is composed of 19 different subunits that form two heteromeric rings, known as "base" and "lid" . It is responsible for binding, deubiquitination and translocation of the protein substrate in the 20S core. The base is composed of nine subunits, 6 of which (Rpt1-6) possess ATPase activity . Rpn1, Rpn2 and Rpn13 are 3 non-ATPases that are necessary for the proper function of the 19S complex. In addition, since they act as polyubiquitin receptors, these subunits are responsible for the recognition of the ubiquitinated protein substrate . The "lid" bridges the gap between the 20S and the 19S proteasomal particles. This structure is evolutionary conserved and consists of nine RPN subunits (Rpn3, 5 -9, 11, 12 and 15). The "lid" is very flexible structure, necessary for the positioning and the deubiquination of the substrate by the deubiquitinating subunit Rpn11 . Thus, the 19S regulatory complex acts as a very versatile device, which facilitates the access of the protein substrate to the core of the 20S proteasome in an ATP-dependent manner.
The 26S/30S proteasome is formed by the 20S catalytic core and the 19S regulatory particle. One or two regulatory complexes may bind on the catalytic core, forming the 26S or the 30S complexes, respectively. The substrates of the 26S proteasome are identified by labeling with multiple ubiquitin molecules. The ubiquitin is attached via a three-step procedure, which requires the action of E1 (ubiquitin activation), E2 (ubiquitin conjugation) and E3 (ubiquitin ligase) ligases. Polymeric ubiquitin chains are produced by the repeated action of the E1, E2 and E3 enzymes. The multi-ubiquitin chains signal the identification of the protein substrate for degradation. Upon recognition of the substrate, the poly-ubiquitin chains are removed by deubiquitinating enzymes (DUBs) . The overall mechanisms of ubiquitination and proteasomal degradation are known as the ubiquitin-proteasome system (UPS system) (Fig. 3).
Figure 3. Overview of the ubiquitin (Ub)/proteasome system and its substrates in relation to aging. Ub conjugation is mediated by a series of enzymes. The Ub-activating enzyme E1 transfers Ub to the active site of the E2 Ub-conjugating enzyme and the E3 Ub-ligase ligate Ub to the target protein. The ubiquitinated protein is targeted to the 26S proteasome for degradation. The 26S proteasome consists of the 20S catalytic core and of one or two 19S regulatory particles. The 20S proteasome consists of 28 subunits that are divided to two outer α and two central β rings. The immunoproteasome is induced in response to the immunomodulatory cytokine interferon-gamma (IFN-gamma) or in response to the increased OS that is observed during aging. The age-related elevation of OS also causes oxidative damage to proteins, such as carbonylation. In addition, the excessive •NO production during aging can lead to aberrant S-nitrosylation/tyrosine nitration. Nitrated proteins are prone to aggregation and may contribute to the onset and progression of various neurodegenerative diseases, including AD or PD. The accumulation of aggregated or carbonylated proteins inhibit proteasomal activity contributing the observed proteasomal dysfunction during aging and to the advancement of age-related pathologies.
Besides the constitutive proteasomes, there are specific specialized proteasomes, formed when the β1, β2 and β5 catalytic subunits become de novo substituted by β1i, β2i and β5i subunits, respectively. These subunits are induced in response to the immunomodulatory cytokine interferon-gamma (IFN-gamma). The immunoproteasomes, as they are termed, besides their main role in antigen presentation, are involved in adaptation to OS and in selective degradation of oxidized proteins during aging, possibly in response to chronic inflammation (as summarized in ).
Proteasome and aging
During aging proteostasis collapses , resulting in the accumulation of denatured, aggregated or oxidized proteins, which in turn causes cellular damage and impairment of tissues . The proteasomes, being the main proteolytic cellular system responsible for the elimination of nonfunctional or excessive proteins, hold a pivotal role in aging .
Young cells and organisms are characterized by an effective preservation of proteostasis. However, this ability is reduced during normal aging. This is evidenced by the increased accumulation of oxidatively modified proteins in senescent cells and tissues, which is indicative of the impairment of protein quality control and of protein degradation systems. Senescent cells have higher levels of proteins bearing modifications, such as oxidative carbonylation, oxidized Met and glycation. Studies in vivo and in vitro have shown that both the expression and function of the proteasome are negatively affected by aging. Proteasome dysfunction during aging results not only due to the reduced expression of proteasome subunits and the impaired assembly of proteasomal complexes, but also because of the aggregated proteins that inhibit its function. Specifically, the reduction of proteasome activity during aging has been detected in numerous aged human tissues (muscles, lenses, skin, lymphocytes) or other mammalian tissues/organs such as the heart, muscles, spine, brain, liver, adipose tissue and retina (reviewed in ).
The activities of the proteasomes decline in senescent human fibroblasts, as a result of a reduction in expression of β subunits . Moreover, it has been shown that the partial inhibition of the proteasomes in young cells causes a p53-mediated premature senescence . On the other hand, the accumulation of damaged proteinaceous materials such as lipofuscin  or of protein aggregates  during aging, impairs proteasome function. Furthermore, studies in D. melanogaster have shown that the age-related disturbances of the 26S proteasome assembly lead to decreased proteasomal activity [240,241]. Notably the naked mole, which is an extremely long-lived rodent, has high levels of proteasome activity, which may contribute to proteostasis maintenance and consequently to the extremely increased lifespan of these animals . Similarly, fibroblasts derived from healthy centenarians have functional proteasomes, with characteristics similar to those of proteasomes from younger donors . Accordingly, human embryonic stem cells (hESCs), that have an unlimited proliferative capacity, exhibit high proteasome activities, as compared to their differentiated counterparts . Recently, the age-related decline of proteasome content and activities, along with the altered proteasome assembly, has been linked with the senescence-related loss of hMSC stemness . Collectively, these studies demonstrate that aging is tightly connected with failures in biosynthesis, assembly and function of the proteasome.
Proteostasis failure is an important determinant of the aging process and is caused by a progressive decline of the respective defense systems. As such, interventions that promote proteostasis may delay aging and reduce the incidence of age-related diseases . For instance, the activation of epidermal growth factor (EGF) signaling extends longevity in nematodes, by increasing the expression of various components of the ubiquitin-proteasome system . Likewise, the enhancement of proteasome activity by deubiquitination inhibitors or by proteasome activators increases the replicative lifespan of yeast Saccharomyces cerevisiae . In addition, the overexpression of the β5 catalytic subunit  or of the 19S subunit Rpn6  confers an increased lifespan in C. elegans.
Similar approaches for activating proteasomes have also proved successful in mammals. The genetic activation of the proteasome has been achieved by the stable overexpression of the catalytic β5 subunit in the fibroblast cell lines WI-38/T and IMR90 . These transfectants have increased ability to degrade oxidized proteins effectively, improved resistance to OS, while the primary IMR90 cells display a 15-20% prolongation of their lifespan. Similarly, the restoration of normal levels of catalytic proteasome subunits ameliorates the aging phenotype in fibroblasts from elderly donors . Overexpression of β5 also promotes proteolysis and resistance to oxidative stress in human epithelial cells  and in promyelocytic leukemia HL60 cells . Similar data have been reported in other cell types using different proteasome subunits. For instance, the overexpression of β6 in human bronchial epithelial Beas2B cells increases the activity of the proteasome and protects against the endoplasmic reticulum (ER) stress induced by cigarette smoke . Moreover, an elevation in expression levels of hUMP1/POMP, a chaperone facilitating proteasome assembly, results in increased proteasome activity and protects the cells from OS . Similarly, an increase of PA28 levels in mouse cardiomyocytes stimulates the degradation of denatured proteins, protecting from heart proteinopathy . Additionally, the overexpression of the regulatory 19S subunit Rpn6/PSMD11 enhances the assembly of 26S proteasome in human embryonic stem cells (hESCs) . Remarkably, it has been recently revealed that overexpression of the β5 proteasome subunit in human Wharton-Jelly derived mesenchymal stem cells (WJ-MSCs) resulted not only in increased proteasome activity and assembly, but also induced the expression of additional 26S proteasome subunits. The enhanced proteasome activity was maintained even after extensive culture, protecting the stem cells form the age-related increase of oxidative damage, as indicated by the reduced levels of ROS and of oxidatively modified proteins. Importantly, proteasome activation doubled the replicative lifespan, improved the expression of the core pluripotency factors and enhanced the differentiation capability towards adipocytes, osteocytes and chondrocytes of both young and senescent WJ-MSCs .
As genetic manipulation is nοt always feasible for clinical applications, there has been an effort towards the identification of natural or synthetic proteasome activators with antioxidant and anti-aging properties. Substances that directly induce the activity of the proteasome include pollen [255,256], oleuropein , curcumin  and the synthetic peptide PAP1 (Proteasome Activating Peptide-1) . A different approach concerns the use of compounds that activate the transcription of proteasomal subunits. It is known that the transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) induces the expression of antioxidant enzymes including proteasomal subunits . Treatment with 18α-glycyrrhetinic acid (18α-GA) activates Nrf2, which in turn induces proteasome function and results in an enhancement of lifespan of both human fibroblasts  and C. elegans nematodes . Likewise, treatment with quercetin increases the CT-L proteasomal activity of human fibroblasts and increases their resistance to OS . Finally, activation of Nrf2 by sulforaphane increases pluripotency and self-renewal capacity of hESCs . The analysis of the role of proteostasis maintenance mechanisms in aging, is essential for the rational design of interventions to improve the quality of human life in old age (‘healthspan’), including the treatment of age-related diseases.
Abundant evidence demonstrates accumulation of products of protein modifications by ROS, RNS and RXS during aging of humans and model organisms and enhanced accumulation of such products in age-related diseases. New methods of analysis, based mainly on the MS technique, became available allowing for more precise identification of protein modifications and perhaps introduction of specific disease markers. Elucidation of the role of such modifications in aging-related changes and in the progress of diseases is more difficult. Are they only markers or aging and diseases or play a primary role in their development? There are reasons to not exclude the second possibility as these modifications adversely affect protein functions and interactions. Prospective and intervention studies may be helpful in this respect and may point to the possible role of specific protein modifications as possible early disease markers.
2D PAGE: two-dimensional polyacrylamide gel electrophoresis; 3-NT: 3-nitrotyrosine; Aβ: Amyloid beta; ACR: acrolein; AD: Alzheimer's disease; ALS: amyotrophic lateral sclerosis; AOPP: Advanced Oxidation Protein Products; DNP: dinitrophenyl; DNPH: dinitrophenylhydrazine; ECM: extracellular matrix; ESI: electro spray ionization; GC: gas chromatography; 4-HNE: 4-Hydroxy-2,3-trans-nonenal; IP: immunoprecipitation; IPL: inferior parietal lobule; MDA: malondialdehyde; MCI: mild cognitive impairment; MPO: myeloperoxidase; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MRM: Multiple Reaction Monitoring; MS: mass spectrometry; NOS: nitric oxide synthase; NS: nitr(os)ative stress; OS: oxidative stress; PD: Parkinson's disease; RCS: reactive carbonyl species; RNS: reactive nitrogen species; ROS: reactive oxygen species; RXS: reactive halogen species; SERCA: sarcoplasmic reticulum Ca2+-ATPase; SOD: superoxide dismutase; αSyn: α-synuclein; Tg: transgene; WB: Western blot; XS: halogenative stress.
Conflicts of Interest
The authors have no conflicts of interest to declare.
This study was performed within the project „Nanomolecular antioxidants: biological basis of targeted therapy of neurodegenerative diseases” (number 2016/22/E/NZ7/00641) financed by National Science Centre (NCN), Poland in a programme „SONATA-BIS 6”. The paper is also a result of realization of research projects OPUS 9 (number 2015/17/B/NZ3/03731) financed by the NCN, Poland.
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