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WIREs Syst Biol Med
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Role of frameshift ubiquitin B protein in Alzheimer's disease

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Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by accumulation of misfolded and aggregated proteins. Since the ubiquitin‐proteasome system (UPS) is the major intracellular protein quality control (PQC) system in eukaryotic cells, it is likely involved in the etiology of AD. The frameshift form of ubiquitin (Ubb+1) accumulates in the neuritic plaques and neurofibrillary tangles in patients with AD. Ubb+1 accumulates in an age‐dependent manner as a result of RNA‐polymerase mediated molecular misreading during transcription, which allows the formation of mutant proteins in the absence of gene mutations. The accumulation of the Ubb+1 protein may act as an endogenous reporter for proteasome dysfunction and a growing number of studies have shown that Ubb+1 may play more important pathogenic roles in AD etiology than previously hypothesized. The yeast Saccharomyces cerevisiae shares many conserved biological processes with all eukaryotic cells, including human neurons. This organism has been regarded as a model system for investigating the fundamental intracellular mechanisms, including those underlying neurodegeneration. We propose here that yeast systems biology approaches, combined with cell and molecular biology approaches will increase the relevant knowledge needed for advancement and elucidation of mechanisms and complex traits, which could provide new targets for therapeutic intervention in AD. WIREs Syst Biol Med 2016, 8:300–313. doi: 10.1002/wsbm.1340 This article is categorized under: Models of Systems Properties and Processes > Organismal Models
Protein quality control (PQC) systems. Intracellular proteins can end up in misfolded conformation by changes in amino acid sequence (due to the genetic mutations), as well as intracellular or extracellular factors (oxidative stress, toxic agents, etc.). The misfolded proteins are prone to organize into complex structures (oligomers, polymers, aggregates and fibers). They are usually recognized by chaperones which promote protein refolding or disaggregation. If the proteins fail to refold into native state, they will be degraded by ubiquitin‐proteasome system (UPS), chaperone mediated autophagy (CMA) or the multivesticular bodies pathway (MVB). However, if the function of UPS, CMA and MVB systems is impaired, or if the proteins have been assembled into insoluble oligomers, the proteins will be removed by macroautophagy.
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(a) The risk factors involved in Alzheimer's disease (AD) onset and progression. Many factors contribute to the likelihood of developing AD. The known genetic causes of AD (left side) are only responsible for fewer than 5% of the total AD cases. The greatest risk factor for AD is advanced age, but many additional nongenetic factors contribute to AD (right side). (b) The neurons in healthy individuals. (c) The intracellular neurofibrillary tangles and extracellular amyloid plaques in and around neurons of AD patients.
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Yeast systems biology as a tool to study neurodegenerative diseases. Different yeast models of interest can be created, such as humanized yeast strains that express or co‐express human proteins of relevance. The strains are then characterized through a systems biology pipeline that includes physiological characterizations in shake‐flasks and in bioreactors (controlled conditions), sampling for cell and molecular biology assays, microscopy and different omics. The collected data are analyzed by bioinformatics and statistics, and integrated with yeast models which help with interpretation and scoring of results. The conclusions can be used to generate the hypotheses that can guide additional experiments or can lead to conclusions that can be tested in vivo and in vitro.
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Ubb+1 properties shift from proteasome substrate to inhibitor. (1) Under nondisease conditions, ubiquitinated Ubb+1 is efficiently degraded by the 26S proteasome. (2) Owing to various causes for instance aging or disease, a decrease in the activity of the proteasome leads to reduced degradation of ubiquitinated Ubb+1. (3) The accumulated ubiquitinated Ubb+1 further inhibits the proteasome activity, which can aggravate the initial decrease in proteasome capacity.
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(a) Ubiquitin covalently modifies the substrate protein via an iso‐peptide bond between the C‐terminal Gly76 residue and selected lysine residues on the substrate. Ubiquitin possesses seven lysine residues that can be ubiquitinated and are involved in polyubiquitin chain formation. (b) The frameshift ubiquitin mutant (Ubb+1) lacks its C‐terminal Gly76 residue and therefore the ability to covalently modify protein substrates. The internal lysine residues of Ubb+1 can still be ubiquitinated by the Gly76 residue of ubiquitin.
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The ubiquitin‐proteasome system (UPS). The proteasome degradation of substrate proteins occurs through an enzymatic cascade of ubiquitination. (1) Ubiquitin is activated by an E1 ubiquitin‐activating enzyme in an ATP‐dependent manner. (2) The activated ubiquitin is subsequently transferred to an E2 ubiquitin‐conjugating enzyme. (3) The E3‐ligating enzyme links ubiquitin from the E2 enzyme to a lysine residue of protein substrate. (4) Additional ubiquitin can be added onto the first to create the polyubiquitin chain on the protein substrate. A chain of at least four ubiquitins (linked via lysine 48) is the primary signal for degradation. (5) Polyubiquitinated protein substrate is recognized and degraded by the 26S proteasome, and the substrate is cleaved into short peptides. (6) The polyubiquitin chain is disassembled by deubiquitinating enzymes (DUBs). The free ubiquitin monomers can be reused to tag other substrates.
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