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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

Left panel: α-secretase (α) cleaves the APP molecules inside the Aβ sequence in a non-amyloidogenic manner, creating a soluble N-terminal part of APP (APPsα) and a C-terminal part (αAPP CTF) which is anchored in the membrane. Subsequently the γ-secretase (γ) cleaves the C-terminal part in a p3 peptide and an APP intracellular domain (AICD). Right panel: β-secretase (β) cleaves the APP at the N-terminus of the Aβ-sequence in an amyloidogenic manner, generating an N-terminal fragment of APP (APPsβ) and a C-terminal part (βAPP CTF). Following, the γ-secretase (γ) cleaves the βAPP-CTF which results in Aβ and AICD. We showed that ubiquitin B+1 (UBB+1) is able to modulate the formation of Aβ plaques in the transgenic (tg) line via γ-secretase, this is shown in the Right panel by the arrowhead (van Tijn et al., 2012; Gentier et al., 2015b).
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Figure 2: Left panel: α-secretase (α) cleaves the APP molecules inside the Aβ sequence in a non-amyloidogenic manner, creating a soluble N-terminal part of APP (APPsα) and a C-terminal part (αAPP CTF) which is anchored in the membrane. Subsequently the γ-secretase (γ) cleaves the C-terminal part in a p3 peptide and an APP intracellular domain (AICD). Right panel: β-secretase (β) cleaves the APP at the N-terminus of the Aβ-sequence in an amyloidogenic manner, generating an N-terminal fragment of APP (APPsβ) and a C-terminal part (βAPP CTF). Following, the γ-secretase (γ) cleaves the βAPP-CTF which results in Aβ and AICD. We showed that ubiquitin B+1 (UBB+1) is able to modulate the formation of Aβ plaques in the transgenic (tg) line via γ-secretase, this is shown in the Right panel by the arrowhead (van Tijn et al., 2012; Gentier et al., 2015b).

Mentions: The amyloid hypothesis focuses on the endoproteolytic cleavage pathway of APP, a transmembrane protein (Glenner and Wong, 1984). This “hypothesis” is supported by the fact that Aβ plaques are present in AD brains and that mutations in the APP gene are involved in the autosomal dominant inherited form of AD (Masters and Selkoe, 2012). APP is a precursor molecule which experience proteolysis to generate Aβ species of different length. Normally, a cascade of endoproteolytic cleavages of APP by α-, β- and γ-secretases results in the production of both non-amyloidogenic (the α-secretase pathway) and amyloidogenic (β-secretase pathway) peptides (Figure 2). The γ-secretase cleavage is a heterogeneous event, so depending on the site of cleavage by this protease Aβ-peptides of different size are generated: Aβ40 and Aβ42 are the most common ones (Haass et al., 2012). The two additional amino acids in Aβ42 compared to Aβ40 render Aβ42 more hydrophobic thereby making it more susceptible aggregate. Due to a higher rate of insolubility and fibrillization, Aβ42 is more abundant than Aβ40 in extracellular plaques. In many types of AD the ratio of Aβ42/Aβ40 is increased (Masters and Selkoe, 2012). This ratio can also be influenced by mutations in the α-secretase (ADAM 10), favoring the amyloidogenic pathway (Suh et al., 2013). Aβ peptides eventually oligomerize to fibrils which eventually accumulate intracellularly, are secreted and promote synaptotoxicity by seeding (Duyckaerts et al., 2009). Three major types of Aβ plaques can be distinguished in AD: diffuse amyloid plaques, dense-core plaques and neuritic plaques (NPs; Serrano-Pozo et al., 2011). Currently, there is still an ongoing debate about which species is exactly more toxic: intracellular oligomers or extracellular plaques? A lot of mutations are found within the γ-secretase complex (PS1, PS2) which cause excessive production of Aβ42. Excessive accumulation of Aβ species and subsequent seeding is the initiating event in the pathogenesis of AD according to this hypothesis. It turned out that the formation of Aβ plaques in a transgenic (tg) model of AD can be modulated by UBB+1 expression via γ-secretase and of this multimeric complex at least the presenilin expression (van Tijn et al., 2012; Gentier et al., 2015b).


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

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

Left panel: α-secretase (α) cleaves the APP molecules inside the Aβ sequence in a non-amyloidogenic manner, creating a soluble N-terminal part of APP (APPsα) and a C-terminal part (αAPP CTF) which is anchored in the membrane. Subsequently the γ-secretase (γ) cleaves the C-terminal part in a p3 peptide and an APP intracellular domain (AICD). Right panel: β-secretase (β) cleaves the APP at the N-terminus of the Aβ-sequence in an amyloidogenic manner, generating an N-terminal fragment of APP (APPsβ) and a C-terminal part (βAPP CTF). Following, the γ-secretase (γ) cleaves the βAPP-CTF which results in Aβ and AICD. We showed that ubiquitin B+1 (UBB+1) is able to modulate the formation of Aβ plaques in the transgenic (tg) line via γ-secretase, this is shown in the Right panel by the arrowhead (van Tijn et al., 2012; Gentier et al., 2015b).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Left panel: α-secretase (α) cleaves the APP molecules inside the Aβ sequence in a non-amyloidogenic manner, creating a soluble N-terminal part of APP (APPsα) and a C-terminal part (αAPP CTF) which is anchored in the membrane. Subsequently the γ-secretase (γ) cleaves the C-terminal part in a p3 peptide and an APP intracellular domain (AICD). Right panel: β-secretase (β) cleaves the APP at the N-terminus of the Aβ-sequence in an amyloidogenic manner, generating an N-terminal fragment of APP (APPsβ) and a C-terminal part (βAPP CTF). Following, the γ-secretase (γ) cleaves the βAPP-CTF which results in Aβ and AICD. We showed that ubiquitin B+1 (UBB+1) is able to modulate the formation of Aβ plaques in the transgenic (tg) line via γ-secretase, this is shown in the Right panel by the arrowhead (van Tijn et al., 2012; Gentier et al., 2015b).
Mentions: The amyloid hypothesis focuses on the endoproteolytic cleavage pathway of APP, a transmembrane protein (Glenner and Wong, 1984). This “hypothesis” is supported by the fact that Aβ plaques are present in AD brains and that mutations in the APP gene are involved in the autosomal dominant inherited form of AD (Masters and Selkoe, 2012). APP is a precursor molecule which experience proteolysis to generate Aβ species of different length. Normally, a cascade of endoproteolytic cleavages of APP by α-, β- and γ-secretases results in the production of both non-amyloidogenic (the α-secretase pathway) and amyloidogenic (β-secretase pathway) peptides (Figure 2). The γ-secretase cleavage is a heterogeneous event, so depending on the site of cleavage by this protease Aβ-peptides of different size are generated: Aβ40 and Aβ42 are the most common ones (Haass et al., 2012). The two additional amino acids in Aβ42 compared to Aβ40 render Aβ42 more hydrophobic thereby making it more susceptible aggregate. Due to a higher rate of insolubility and fibrillization, Aβ42 is more abundant than Aβ40 in extracellular plaques. In many types of AD the ratio of Aβ42/Aβ40 is increased (Masters and Selkoe, 2012). This ratio can also be influenced by mutations in the α-secretase (ADAM 10), favoring the amyloidogenic pathway (Suh et al., 2013). Aβ peptides eventually oligomerize to fibrils which eventually accumulate intracellularly, are secreted and promote synaptotoxicity by seeding (Duyckaerts et al., 2009). Three major types of Aβ plaques can be distinguished in AD: diffuse amyloid plaques, dense-core plaques and neuritic plaques (NPs; Serrano-Pozo et al., 2011). Currently, there is still an ongoing debate about which species is exactly more toxic: intracellular oligomers or extracellular plaques? A lot of mutations are found within the γ-secretase complex (PS1, PS2) which cause excessive production of Aβ42. Excessive accumulation of Aβ species and subsequent seeding is the initiating event in the pathogenesis of AD according to this hypothesis. It turned out that the formation of Aβ plaques in a transgenic (tg) model of AD can be modulated by UBB+1 expression via γ-secretase and of this multimeric complex at least the presenilin expression (van Tijn et al., 2012; Gentier et al., 2015b).

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