complex(GO:"proteasome complex")
In a parallel experiment using a cell culture model, Congo red was found to increase proteasomal activity in cells expressing a polyglutamine protein but not in cells expressing a control protein (Sanchez et al., 2003). PubMed:14556719
However, Abeta has been demonstrated to reduce proteasome activity in reticulocyte lysates (Gregori et al., 1995), suggesting that increased levels of the peptide could underlie the reduction in UPS function observed in the AD brain. PubMed:14556719
It has been shown that Abeta can be degraded by the proteasome in cultured neurons and astrocytes, and reatment with the proteasome inhibitor lactacystin decreased viability of cells exposed to Abeta (Lopez Salon et al., 2003). PubMed:14556719
They present evidence that paired helical filaments obtained from AD brain or generated in vitro can inhibit proteasome function and that in AD brain tissue these filaments coimmunoprecipitate with the proteasome (Keck et al., 2003). PubMed:14556719
The degradation signal that is recognized by the 26S proteasome complex is made of a Lys48 polyubiquitin chain. PubMed:14556719
Conjugation to other Lys residues, Lys63 for example, serves nonproteolytic functions of the system, such as activation of transcription PubMed:14556719
The proteasome activity in the mammalian brain decreases with increasing age (Keller et al., 2002), suggesting that the aged brain is less able to handle the aberrantly folded Abeta PubMed:14556719
Concomitantly, it reduced the inhibition of the proteasome and the activation of caspase 12 that are induced by accumulation of the polyglutamine-containing fragment PubMed:14556719
An important finding, however, in that respect is that aggregated and even monomeric alphaSYN bind to the S6' proteasome subunit and inhibit proteasomal function (Snyder et al., 2003). PubMed:14556719
Concomitantly, it reduced the inhibition of the proteasome and the activation of caspase 12 that are induced by accumulation of the polyglutamine-containing fragment PubMed:14556719
In a cell culture model, they overexpressed mutant Huntingtin and observed proteasomal inhibition accompanied by cell cycle arrest PubMed:14556719
An important finding, however, in that respect is that aggregated and even monomeric alphaSYN bind to the S6' proteasome subunit and inhibit proteasomal function (Snyder et al., 2003). PubMed:14556719
They found that the proteasome catalytic activity was decreased in neuroblastoma cells following 1 week of expression of a mutant SOD1 gene. PubMed:14556719
In the other model, the expression of mutant SOD1 alone was sufficient to induce oxidative stress, giving rise to increased proteasome activity, possibly due to the need to remove oxidatively damaged proteins (Hyun et al., 2003). PubMed:14556719
This can be inhibited by a-syn oligomers: oligomers were shown to inhibit proteasomal activity, which was blocked by addition of antibodies that neutralized the interaction [87]. PubMed:28803412
Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051
Sixth, aggregates and mutant forms of α-synuclein disrupt the proteasome in dopaminergic neurons. PubMed:30116051
Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 . PubMed:30116051
Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051
An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493
We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934
Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin PubMed:26692334
It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809
It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809
PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance. PubMed:26692334
We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. PubMed:26041011
For instance, phosphorylated insoluble tau proteins dampen 26S proteasome activity, while activation of the UPS attenuates tauopathy [27] PubMed:29758300
Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300
Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190
That is, in areas where NFTs formed abundantly, including hippocampus and parahippocampal gyrus and superior and middle temporal gyri, proteasome activity (as assessed by chymortrypsinlike and postglutamyl peptidases) appeared to be most affected, whereas occipital gyri and cerebellum, which often have few or no NFTs, were least affected (Keller et al. 2000). PubMed:22908190
In vitro experiments further showed that aggregated (recombinant) tau—but not nonaggregated (monomeric) tau—can inhibit the proteasome activity. PubMed:22908190
PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000). PubMed:22908190
Moreover, soluble Ab oligomers themselves can inhibit proteasomal activity (Tseng et al. 2008). PubMed:22908190
AD is the most common of numerous age-associated brain diseases, and the activity of brain proteasomes appears to decline with age (Keller et al. 2002). PubMed:22908190
Beyond an age-related reduction (Keller et al. 2002), proteasome activities decrease in AD in a brain region–specific manner, particularly in hippocampus, parahippocampal gyrus, superior and middle temporal gyri, and the inferior parietal lobule (Keller et al. 2000), areas that are especially critical for long-term memory formation. PubMed:22908190
Based on these various findings, it has been speculated that small aggregates of PHFs may bind to the cap portion of the 26S proteasome and inhibit its activity PubMed:22908190
Another study of AD brain tissues showed that hyperphosphorylated tau was bound to the proteasome, presumably to the 19S cap portion, and the more tau that was bound, the more that proteasomes appeared to be inhibited (Keck et al. 2003). PubMed:22908190
Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190
Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136
Regulation of receptor subunits by the proteasome, the large pro- tein complex that proteolytically degrades unneeded proteins, has also been demonstrated [113,114]. PubMed:22040696
Furthermore, the proteasome in- directly regulates synaptic transmission mediated by AChRs via regu- lation of RIC-3 [113]. PubMed:22040696
Furthermore, the proteasome in- directly regulates synaptic transmission mediated by AChRs via regu- lation of RIC-3 [113]. PubMed:22040696
Degradation of polyubiquitinated substrates is carried out by a large protease complex, the 26S proteasome that does not generally recognize nonmodified substrates PubMed:14556719
Degradation of polyubiquitinated substrates is carried out by a large protease complex, the 26S proteasome that does not generally recognize nonmodified substrates PubMed:14556719
In one established and exceptional case, however that of the polyamine synthesizing enzyme ornithine decarboxylase (ODC), the proteasome recognizes and degrades the substrate following its association with another protein, antizyme, without prior ubiquitination PubMed:14556719
The proteasome is a large, multicatalytic protease that degrades polyubiquitinated proteins to small peptides PubMed:14556719
The UPS can be regulated at the level of ubiquitination or at the level of proteasome activity PubMed:14556719
It has been shown that Abeta can be degraded by the proteasome in cultured neurons and astrocytes, and reatment with the proteasome inhibitor lactacystin decreased viability of cells exposed to Abeta (Lopez Salon et al., 2003). PubMed:14556719
The proteasome activity in the mammalian brain decreases with increasing age (Keller et al., 2002), suggesting that the aged brain is less able to handle the aberrantly folded Abeta PubMed:14556719
They found that the proteasome catalytic activity was decreased in neuroblastoma cells following 1 week of expression of a mutant SOD1 gene. PubMed:14556719
Neuronal autophagy has been found to occur following chronic, low-grade proteasomal inhibition in cultured neuroblastoma cells (Ding et al., 2003) and may reflect activation of the lysosomal system as cells try to protect themselves during stress (Larsen and Sulzer, 2002). PubMed:14556719
Lunkes and colleagues demonstrated that truncated Huntingtin, which has undergone proteolytic cleavage in the cytoplasm, accumulates more rapidly if the proteasome is pharmacologically inhibited (Lunkes et al., 2002). PubMed:14556719
This observation suggests that chain binding and cleavage from the protein substrate are tightly coordinated by the proteasome, and may help to prevent situations such as premature chain cleavage by Rpn11, which could result in the release of the substrate before it becomes actively engaged to the proteasome. PubMed:24457024
Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051
An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493
We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934
We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934
It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809
It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809
We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. PubMed:26041011
PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance. PubMed:26692334
Since the initial finding of proteasome-dependent degradation of α-synuclein [58], significant efforts have been made to clarify the modes of α-synuclein metabolism PubMed:29758300
Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300
The proteasome selectively degrades normal proteins (mainly those with short half-lives) and abnormal proteins, which are earmarked for elimination by a process involving their conjugation to ubiquitin (Ub; Goldberg 2003). PubMed:22908190
Proteins tagged with chains of four or more K48-linked multiubiquitins provide the strongest signal for degradation by the 26S proteasome, because a chain of at least four Ub moieties is required for substrate recognition by the 26S proteasome complex. PubMed:22908190
AD is the most common of numerous age-associated brain diseases, and the activity of brain proteasomes appears to decline with age (Keller et al. 2002). PubMed:22908190
Beyond an age-related reduction (Keller et al. 2002), proteasome activities decrease in AD in a brain region–specific manner, particularly in hippocampus, parahippocampal gyrus, superior and middle temporal gyri, and the inferior parietal lobule (Keller et al. 2000), areas that are especially critical for long-term memory formation. PubMed:22908190
PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000). PubMed:22908190
That is, in areas where NFTs formed abundantly, including hippocampus and parahippocampal gyrus and superior and middle temporal gyri, proteasome activity (as assessed by chymortrypsinlike and postglutamyl peptidases) appeared to be most affected, whereas occipital gyri and cerebellum, which often have few or no NFTs, were least affected (Keller et al. 2000). PubMed:22908190
Another study of AD brain tissues showed that hyperphosphorylated tau was bound to the proteasome, presumably to the 19S cap portion, and the more tau that was bound, the more that proteasomes appeared to be inhibited (Keck et al. 2003). PubMed:22908190
During the induction of long-term facilitation in the snail, the regulatory subunit of cAMP-dependent protein kinase (PKA) is ubiquitinated and degraded by the proteasome, generating persistently activated PKA (Hegde et al. 1993). PubMed:22908190
It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes. PubMed:22908190
As regards the proteasome, both the ATP-dependent 26S proteasome and the ATP-independent 20S proteasome have been reported to degrade normal, soluble tau (Cardozo et al. 2002; Zhang et al. 2005). PubMed:22908190
Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190
Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190
There have been fewer efforts to manipulate UPS function for therapeutic benefit in neurodegenerative disease, but it was recently shown that use of a proteasome activator enhanced survival in an in vitro model of Huntington’s disease [58], suggesting that augmenting other routes of protein degradation may also provide neuroprotection. PubMed:18930136
Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136
Cellular stresses such as polyQ expression, proteasome impairment, oxidative stress, and increased misfolded protein burden activate transcription and translation of p62, suggesting that it functions broadly in stress situations [83,84] PubMed:18930136
BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.
If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.