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Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease.

Gentier RJ, van Leeuwen FW - Front Mol Neurosci (2015)

Bottom Line: Other medium-risk factors such as triggering receptor expressed on myeloid cells 2 (TREM2) and nine low risk factors from Genome Wide Association Studies (GWAS) were associated with AD.We reported that DNA-RNA sequence differences in several genes including ubiquitin do occur in AD, the resulting misframed protein of which accumulates in the neurofibrillary tangles (NFTs).Progress in this field is discussed and modulating the activity of the UPS opens an attractive avenue of research towards slowing down the development of AD and ameliorating its effects by discovering prime targets for AD therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht, Netherlands.

ABSTRACT
Amyloid β (Aβ) plaque formation is a prominent cellular hallmark of Alzheimer's disease (AD). To date, immunization trials in AD patients have not been effective in terms of curing or ameliorating dementia. In addition, γ-secretase inhibitor strategies await clinical improvements in AD. These approaches were based upon the idea that autosomal dominant mutations in amyloid precursor protein (APP) and Presenilin 1 (PS1) genes are predictive for treatment of all AD patients. However most AD patients are of the sporadic form which partly explains the failures to treat this multifactorial disease. The major risk factor for developing sporadic AD (SAD) is aging whereas the Apolipoprotein E polymorphism (ε4 variant) is the most prominent genetic risk factor. Other medium-risk factors such as triggering receptor expressed on myeloid cells 2 (TREM2) and nine low risk factors from Genome Wide Association Studies (GWAS) were associated with AD. Recently, pooled GWAS studies identified protein ubiquitination as one of the key modulators of AD. In addition, a brain site specific strategy was used to compare the proteomes of AD patients by an Ingenuity Pathway Analysis. This strategy revealed numerous proteins that strongly interact with ubiquitin (UBB) signaling, and pointing to a dysfunctional ubiquitin proteasome system (UPS) as a causal factor in AD. We reported that DNA-RNA sequence differences in several genes including ubiquitin do occur in AD, the resulting misframed protein of which accumulates in the neurofibrillary tangles (NFTs). This suggests again a functional link between neurodegeneration of the AD type and loss of protein quality control by the UPS. Progress in this field is discussed and modulating the activity of the UPS opens an attractive avenue of research towards slowing down the development of AD and ameliorating its effects by discovering prime targets for AD therapeutics.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the UPS. The degradation process by the UPS can be divided into five steps. (a) Beginning with monomeric ubiquitin (orange circles). Ubiquitin becomes activated in an ATP-dependent manner by E1. (b) Activated ubiquitin (red circles) is conjugated by E2 enzymes. (c) Thereafter, UBB is transferred to an internal lysine of the target protein by E3 ligases. Following, activated and conjugated ubiquitin binds to the abnormal protein forming the polyubiquitin-protein conjugate. (d) Subsequently, the polyubiquitin-protein conjugate is degraded by the 26S proteasome complex (Figure 5) by an ATP-dependent process (Peth et al., 2013). The abnormal protein is cleaved into short peptide fragments (orange pointed bars) and the polyubiquitin chain is released (yellow circles). (e) The polyubiquitin chain is split by de-ubiquitination enzymes into monomeric ubiquitins. For details, see Layfield et al. (2005).
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Figure 5: Schematic representation of the UPS. The degradation process by the UPS can be divided into five steps. (a) Beginning with monomeric ubiquitin (orange circles). Ubiquitin becomes activated in an ATP-dependent manner by E1. (b) Activated ubiquitin (red circles) is conjugated by E2 enzymes. (c) Thereafter, UBB is transferred to an internal lysine of the target protein by E3 ligases. Following, activated and conjugated ubiquitin binds to the abnormal protein forming the polyubiquitin-protein conjugate. (d) Subsequently, the polyubiquitin-protein conjugate is degraded by the 26S proteasome complex (Figure 5) by an ATP-dependent process (Peth et al., 2013). The abnormal protein is cleaved into short peptide fragments (orange pointed bars) and the polyubiquitin chain is released (yellow circles). (e) The polyubiquitin chain is split by de-ubiquitination enzymes into monomeric ubiquitins. For details, see Layfield et al. (2005).

Mentions: The conjugation of UBB to the internal lysine residues (K) of the target protein is mediated by a cascade of E1-activating, E2-conjugating, E3-ligating and E4-elongating enzymes, which are stepwise described in Figure 5. UBB is generated from a precursor protein which is cleaved by ubiquitin C-terminal hydrolases (UCHs). UBB becomes activated in an ATP-dependent manner by the enzyme E1 via a high-energy thiolester bond between the carboxyl group of UBB and the active-site cysteine of E1 enzyme (Pickart, 2001). Subsequently, activated UBB is conjugated to the active site of an E2 ubiquitin-conjugation enzyme by a transthioesterification reaction. Currently, at least 30 different E2 enzymes have been described in the human genome (Bhowmick et al., 2013). Thereafter, UBB is transferred to an internal lysine of the target protein by E3 ubiquitin-protein ligases. There are at least 600 E3 ligases encoded in the human genome (Bhowmick et al., 2013). E3 ligases mediate the ligation between UBB and the target protein resulting in the ubiquitination of the target protein (Ciechanover and Kwon, 2015). Two different types of E3 enzymes are known: one type, the Homologous to E6-associated protein C-terminus (HECT) binds the E2-enzymes as well as the target protein and serves in this way as an intermediate docking station for UBB. A second type of E3-enzyme is the Real Interesting New Gene (RING) finger containing E3-ligase. In this instance, UBB is transferred directly from the E2-complex to the target protein by the RING-E3 ligase.


Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease.

Gentier RJ, van Leeuwen FW - Front Mol Neurosci (2015)

Schematic representation of the UPS. The degradation process by the UPS can be divided into five steps. (a) Beginning with monomeric ubiquitin (orange circles). Ubiquitin becomes activated in an ATP-dependent manner by E1. (b) Activated ubiquitin (red circles) is conjugated by E2 enzymes. (c) Thereafter, UBB is transferred to an internal lysine of the target protein by E3 ligases. Following, activated and conjugated ubiquitin binds to the abnormal protein forming the polyubiquitin-protein conjugate. (d) Subsequently, the polyubiquitin-protein conjugate is degraded by the 26S proteasome complex (Figure 5) by an ATP-dependent process (Peth et al., 2013). The abnormal protein is cleaved into short peptide fragments (orange pointed bars) and the polyubiquitin chain is released (yellow circles). (e) The polyubiquitin chain is split by de-ubiquitination enzymes into monomeric ubiquitins. For details, see Layfield et al. (2005).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4557111&req=5

Figure 5: Schematic representation of the UPS. The degradation process by the UPS can be divided into five steps. (a) Beginning with monomeric ubiquitin (orange circles). Ubiquitin becomes activated in an ATP-dependent manner by E1. (b) Activated ubiquitin (red circles) is conjugated by E2 enzymes. (c) Thereafter, UBB is transferred to an internal lysine of the target protein by E3 ligases. Following, activated and conjugated ubiquitin binds to the abnormal protein forming the polyubiquitin-protein conjugate. (d) Subsequently, the polyubiquitin-protein conjugate is degraded by the 26S proteasome complex (Figure 5) by an ATP-dependent process (Peth et al., 2013). The abnormal protein is cleaved into short peptide fragments (orange pointed bars) and the polyubiquitin chain is released (yellow circles). (e) The polyubiquitin chain is split by de-ubiquitination enzymes into monomeric ubiquitins. For details, see Layfield et al. (2005).
Mentions: The conjugation of UBB to the internal lysine residues (K) of the target protein is mediated by a cascade of E1-activating, E2-conjugating, E3-ligating and E4-elongating enzymes, which are stepwise described in Figure 5. UBB is generated from a precursor protein which is cleaved by ubiquitin C-terminal hydrolases (UCHs). UBB becomes activated in an ATP-dependent manner by the enzyme E1 via a high-energy thiolester bond between the carboxyl group of UBB and the active-site cysteine of E1 enzyme (Pickart, 2001). Subsequently, activated UBB is conjugated to the active site of an E2 ubiquitin-conjugation enzyme by a transthioesterification reaction. Currently, at least 30 different E2 enzymes have been described in the human genome (Bhowmick et al., 2013). Thereafter, UBB is transferred to an internal lysine of the target protein by E3 ubiquitin-protein ligases. There are at least 600 E3 ligases encoded in the human genome (Bhowmick et al., 2013). E3 ligases mediate the ligation between UBB and the target protein resulting in the ubiquitination of the target protein (Ciechanover and Kwon, 2015). Two different types of E3 enzymes are known: one type, the Homologous to E6-associated protein C-terminus (HECT) binds the E2-enzymes as well as the target protein and serves in this way as an intermediate docking station for UBB. A second type of E3-enzyme is the Real Interesting New Gene (RING) finger containing E3-ligase. In this instance, UBB is transferred directly from the E2-complex to the target protein by the RING-E3 ligase.

Bottom Line: Other medium-risk factors such as triggering receptor expressed on myeloid cells 2 (TREM2) and nine low risk factors from Genome Wide Association Studies (GWAS) were associated with AD.We reported that DNA-RNA sequence differences in several genes including ubiquitin do occur in AD, the resulting misframed protein of which accumulates in the neurofibrillary tangles (NFTs).Progress in this field is discussed and modulating the activity of the UPS opens an attractive avenue of research towards slowing down the development of AD and ameliorating its effects by discovering prime targets for AD therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht, Netherlands.

ABSTRACT
Amyloid β (Aβ) plaque formation is a prominent cellular hallmark of Alzheimer's disease (AD). To date, immunization trials in AD patients have not been effective in terms of curing or ameliorating dementia. In addition, γ-secretase inhibitor strategies await clinical improvements in AD. These approaches were based upon the idea that autosomal dominant mutations in amyloid precursor protein (APP) and Presenilin 1 (PS1) genes are predictive for treatment of all AD patients. However most AD patients are of the sporadic form which partly explains the failures to treat this multifactorial disease. The major risk factor for developing sporadic AD (SAD) is aging whereas the Apolipoprotein E polymorphism (ε4 variant) is the most prominent genetic risk factor. Other medium-risk factors such as triggering receptor expressed on myeloid cells 2 (TREM2) and nine low risk factors from Genome Wide Association Studies (GWAS) were associated with AD. Recently, pooled GWAS studies identified protein ubiquitination as one of the key modulators of AD. In addition, a brain site specific strategy was used to compare the proteomes of AD patients by an Ingenuity Pathway Analysis. This strategy revealed numerous proteins that strongly interact with ubiquitin (UBB) signaling, and pointing to a dysfunctional ubiquitin proteasome system (UPS) as a causal factor in AD. We reported that DNA-RNA sequence differences in several genes including ubiquitin do occur in AD, the resulting misframed protein of which accumulates in the neurofibrillary tangles (NFTs). This suggests again a functional link between neurodegeneration of the AD type and loss of protein quality control by the UPS. Progress in this field is discussed and modulating the activity of the UPS opens an attractive avenue of research towards slowing down the development of AD and ameliorating its effects by discovering prime targets for AD therapeutics.

No MeSH data available.


Related in: MedlinePlus