Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Lam, Y. Amy; Pickart, Cecile M.; Alban, Andrew; Landon, Michael; Jamieson, Craig; Ramage, R.; Mayer, R. John; Layfield, Robert

doi:10.1073/pnas.170173897

Cited by 303 publications

(231 citation statements)

References 36 publications

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“…Ub ligation by Cdc34 requires the alignment of two Ub molecules in a manner that permits Lys-48 of one molecule (the acceptor) to react with Gly-76 of the other (the donor) molecule bound to the catalytic Cys-93 of Cdc34, as shown by the ability of Cdc34 to form an Ub dimer composed of the Ub K48R donor and the Ub ϩ1 acceptor [deficient in thiol-ester formation (19); data not shown]. How might juxtaposed Cdc34 molecules work to promote Ub ligation?…”

Section: Discussionmentioning

confidence: 99%

Proximity-induced activation of human Cdc34 through heterologous dimerization

Gazdoiu

Yamoah

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cdc34 is an E2-conjugating enzyme required for catalyzing the polyubiquitination reaction mediated by the Skp1⅐CUL1⅐F-box (SCF) protein E3 ubiquitin (Ub) ligase. Here, we show that the activity of human Cdc34 in the Ub-Ub ligation reaction was enhanced dramatically by SCF's core Ub ligase module, composed of a heterodimeric complex formed by the ROC1 RING finger protein and the CUL1 C terminus that contains a Nedd8 moiety covalently conjugated at K720. Unexpectedly, we found that N-terminal fusion of a GST moiety to human Cdc34 generated dimeric GSTCdc34 that was constitutively active in supporting the assembly of K48-linked polyUb chains independently of SCF. Furthermore, fusion of a FK506-binding protein (FKBP) to the N terminus of human Cdc34 yielded FKBP-Cdc34 that was induced to form a dimer upon treatment with the chemical inducer AP20187. The AP20187-induced dimeric form of FKBP-Cdc34 was substantially more active than the monomer in catalyzing Ub-Ub ligation. Thus, juxtaposition of human Cdc34 activates its catalytic capability, suggesting that the SCF-mediated polyubiquitination reaction may require the conversion of Cdc34 from an inactive monomer to a highly active dimeric form.SCF ͉ ubiquitination U biquitin (Ub)-dependent proteolysis is a remarkably intricate biochemical process in which the 26S proteasome recognizes and subsequently degrades a target protein tagged with lysine-48-linked polyUb chains, generated through a modification reaction known as ubiquitination. Ubiquitination requires activation of monomeric Ub through formation of an initial thiol-ester bond with the E1 activating enzyme followed by transfer of the thiol-ester-linked Ub to an E2 conjugating enzyme (1). The enzymatic generation of signaling Ub chains attached to a substrate is mediated typically by an E3 Ub ligase, which contains either a HECT domain or a RING finger motif and functions by recognizing both the substrate and an E2 (2).The Skp1⅐CUL1⅐F-box protein⅐ROC1 (SCF) complex is a prototype of cullin (CUL)-based RING E3 ligases that are defined by two signature components: a CUL-family molecule and its RING finger partner ROC1͞Rbx1͞Hrt1 (reviewed in ref.3). SCF utilizes the CUL1 scaffold to anchor a substratetargeting module (comprised of the Skp1⅐F-box protein heterodimer) and to tether ROC1 (via the CUL domain), respectively (4 -6). As a result of this multisubunit interaction, an F-box protein (member of a large family of substrate-targeting molecules) is placed in proximity to ROC1, which functions to recruit an E2 conjugating enzyme (7-9), thereby initiating the ubiquitination of a bound substrate. As revealed by a large body of genetic and biochemical experiments, the SCF and other CUL-based RING E3 ligases are activated by conjugation of Nedd8 to a conserved lysine residue within a CUL protein (a process termed neddylation) (3), which mechanistically parallels ubiquitination.In budding yeast, the activity of SCF requires Cdc34, a class II E2 Ub-conjugating enzyme that catalyzes the formation of K48-linked polyUb cha...

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Section: Discussionmentioning

confidence: 99%

Proximity-induced activation of human Cdc34 through heterologous dimerization

Gazdoiu

Yamoah

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…7 The altered C-terminus abrogates the ability of UbB þ 1 to tag other substrates without affecting its polyubiquitination. 8,9 Polyubiquitinated UbB þ 1 is refractory to deubiquitination and impairs proteasome function. 8 Accordingly, induction of UbB þ 1 results in UPP dysfunction and neuronal cell death.…”

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confidence: 99%

Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration

et al. 2007

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A dinucleotide deletion in human ubiquitin (Ub) B messenger RNA leads to formation of polyubiquitin (UbB) þ 1, which has been implicated in neuronal cell death in Alzheimer's and other neurodegenerative diseases. Previous studies demonstrate that UbB þ 1 protein causes proteasome dysfunction. However, the molecular mechanism of UbB þ 1-mediated neuronal degeneration remains unknown. We now report that UbB þ 1 causes neuritic beading, impairment of mitochondrial movements, mitochondrial stress and neuronal degeneration in primary neurons. Transfection of UbB þ 1 induced a buildup of mitochondria in neurites and dysregulation of mitochondrial motor proteins, in particular, through detachment of P74, the dynein intermediate chain, from mitochondria and decreased mitochondria-microtubule interactions. Altered distribution of mitochondria was associated with activation of both the mitochondrial stress and p53 cell death pathways. These results support the hypothesis that neuritic clogging of mitochondria by UbB þ 1 triggers a cascade of events characterized by local activation of mitochondrial stress followed by global cell death. Furthermore, UbB þ 1 small interfering RNA efficiently blocked expression of UbB þ 1 protein, attenuated neuritic beading and preserved cellular morphology, suggesting a potential neuroprotective strategy for certain neurodegenerative disorders.

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“…80 Aberrant protein degradation through the ubiquitin-proteasome pathway has also been suggested to be one of the etiologies in AD. 81 Previous AD studies have found weak association with SNPs in TRIB3, 82,83 a negative regulator of the inflammation response inducing gene NF-kB, 84 located in our linkage interval. We analyzed SNPs in TRIB3 in the present association analysis and our lowest obtained P-value was 0.10.…”

Section: Discussionmentioning

confidence: 58%

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

et al. 2010

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This study aimed at identifying novel susceptibility genes for a mixed phenotype of Alzheimer's disease and vascular dementia. Results from a genome scan showed strongest linkage to 20p13 in 18 families, and subsequent fine mapping was performed with both microsatellites and single-nucleotide polymorphisms in 18 selected candidate transcripts in an extended sample set of 30 families. The multipoint linkage peak was located at marker rs2144151 in the ANGPT4 gene, which is a strong candidate gene for vascular disease because of its involvement in angiogenesis. Although the significance of the linkage decreased, we find this result intriguing, considering that we included additional families, and thus the reduced linkage signal may be caused by genetic heterogeneity.

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Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Cited by 303 publications

References 36 publications

Proximity-induced activation of human Cdc34 through heterologous dimerization

Proximity-induced activation of human Cdc34 through heterologous dimerization

Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

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