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Review
. 2015 Sep 2:8:47.
doi: 10.3389/fnmol.2015.00047. eCollection 2015.

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

Romina J Gentier  1 , Fred W van Leeuwen  1
Affiliations
Review

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

Romina J Gentier et al. Front Mol Neurosci. .

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.

Keywords: amyloid precursor protein; frameshift mutation; mRNA surveillance; molecular misreading; neurodegeneration; proteasome; tau.

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Figures

Figure 1
Figure 1
Early [<65 years; early-onset AD (EOAD)] and late onset [>65 years; late-onset AD (LOAD)] forms of Alzheimers disease (AD) subdivided in familial, sporadic and autosomal dominant forms of AD. “Familial” means that AD was observed in relatives of the first degree. In familial EOAD, the majority (54%) is not yet linked to a chromosome, whereas 6% is inherited in an autosomal dominant way and linked to chromosome 14 (PS1), chromosome 1 (PS2) and chromosome 21 amyloid precursor protein (APP; Harvey et al., ; Mercy et al., 2008). In familial LOAD, the majority is not yet linked to a chromosome, whereas a minority is inherited in an autosomal dominant way. A subset has been linked to chromosome 12 (Pericak-Vance et al., 1997). Figure was updated in 2015.
Figure 2
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., ; Gentier et al., 2015b).
Figure 3
Figure 3
Simplified scheme of the multiubiquitination process of proteasome substrates. In the ubiquitin proteasome system (UPS), a substrate (= a degron, such as a misfolded protein) is (poly)ubiquitinated via a number of enzymatic steps (E1, E2 and E3). The C-terminal glycine (G76) of the UBB molecule will attach to lysine moieties (K) at positions 29, 48 and 63 which are involved in multiubiquitination and degradation. The UBB molecule “on top” of the target protein prone for degradation can be ubiquitinated itself, developing a multiubiquitination chain with at least four residues to be efficient for triggering proteasomal degradation (left panel). A GAGAG motif is present at the C-terminus of UBB and a dinucleotide deletion (ΔGU) occurs adjacent to this motif which results in an 20 amino acids extension (red bar), called UBB+1 (see Figure 4). This causes the absence of G76, necessary for binding to the target protein, and consequently it is not able to ubiquitinate (Ciechanover and Kwon, 2015). Interestingly, E3 enzymes are able to form a “forked” polyubiquitin chain in which two ubiquitin chains are linked ot adjacent lysines on a preceding ubiquitin moiety (e.g., K29, K48 and K63). These forked polyubiquitin chains are relatively resistant to degradation by the 26S proteasome (Kim et al., 2009).
Figure 4
Figure 4
Assembly-line slippage. Loss of two bases [ΔGU, ΔGA and other ones (van Den Hurk et al., 2001)] in the mRNA garbles the rest of the sequence (Vogel, 1998). Non-sense mRNA decay (NMD) requires a downstream intron (Maquat, 2015) that is present in APP, Neurofilament H and MAP2b genes. However, in the UBB gene, this downstream intron is lacking and the misframed transcript apparently escapes NMD. As shown in Figure 3 thereby the essential C-terminus is lost. In (A–C) the resulting UBB+1 accumulation in neurofibrillary tangles (NFTs) (triangle) of the hippocampus of an AD patient and a similar one in Pick’s disease (D,E) in Pick bodies of CA1 in the hippocampus is shown. Note in (A) the presence of neuritic plaques (NPs) indicated by a star. (F,G) Neurofilament H transcripts apparently undergo a similar process (exon 1. aa. VGAARDSRAA), the resulting NFH+1 protein accumulates in CA1 of the hippocampus of AD patients (triangle). A similar reaction was found for MAP2B+1 (for details, see van Leeuwen et al., 2000). Of course these immunohistochemical data require many controls to avoid cross reactivity (Swaab et al., 1977) as was done for UBB+1. (A–C) 50 μm thick Vibratome sections, (D–F) 6 μm think paraffin sections.
Figure 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).
Figure 6
Figure 6
A representation of the 26S proteasome complex based on Kostova and Wolf (2003). The lid consists of eight non-ATP-ase subunits, the base consists of 6 ATP-ase and 3 non-ATP-ase subunits. Please note here that the yeast nomenclature is used. The catalytic core (blue) is a barrel-like structure and consists of four stacked heptameric rings. The function of many of the lid, base and ATPase ring subunits such as Rpt3 (red); Rpt 5 (purple); Rpn 11 (blue) have been described. For details, see text, Tsakiri and Trougakos (2015).
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