Family-Based Association between Alzheimer's Disease and Variants in<i>UBQLN1</i>

Bertram, Lars; Hiltunen, Mikko; Parkinson, Michele; Ingelsson, Martin; Lange, Christoph; Ramasamy, Karunya; Mullin, Kristina; Menon, R; Sampson, Andrew; Hsiao, Monica; Elliott, Kathryn; Veliçelebi, Gönül; Moscarillo, T J; Hyman, Bradley T.; Wagner, Steven L.; Becker, Kurt; Blacker, Deborah; Tanzi, Rudolph E.

doi:10.1056/nejmoa042765

Cited by 220 publications

(216 citation statements)

References 31 publications

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“…There is strong evidence that both ubiquilin 1 and ubiquilin 2 interact with the proteasome through the Ubl domain (59) and that ubiquilin 1 binds polyubiquitinated chains through the Uba domain (60,61). Furthermore, these proteins play a role in diseases caused by protein aggregation in neurodegeneration (62)(63)(64)(65), which suggests that ubiquilins are involved in protein homeostasis within the cytoplasm. Additionally, ubiquilins are involved in autophagy mediated protein degradation (66,67).…”

Section: Discussionmentioning

confidence: 99%

Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Coffey

Shi²,

Long

et al. 2016

Journal of Biological Chemistry

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Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism, growth, and proliferation. mTORC1 has been implicated in many diseases such as cancer, diabetes, and neurodegeneration, and is a target to prolong lifespan. Here we report a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. In contrast, rapamycin preferentially inhibits the phosphorylation of p70S6k and blocks 35% of translation. Cbz-B3A does not appear to bind directly to mTORC1, but instead binds to ubiquilins 1, 2, and 4. Knockdown of ubiquilin 2, but not ubiquilins 1 and 4, decreases the phosphorylation of 4EBP1, suggesting that ubiquilin 2 activates mTORC1. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. Cbz-B3A slows cellular growth of some human leukemia cell lines, but is not cytotoxic. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. We propose that Cbz-B3A reveals a previously unappreciated regulatory pathway coordinating cytosolic protein quality control and mTORC1 signaling.

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Section: Discussionmentioning

confidence: 99%

Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Coffey

Shi²,

Long

et al. 2016

Journal of Biological Chemistry

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“…Bertram et al 8 have examined five UBQLN1 SNPs encompassing in a single haplotype block and found significant associations with three SNPs in intron 6, 8 and 9. The strongest association was observed with the intron 8 SNP followed by intron 9 and 6 SNPs using family-based association and pedigree disequilibrium tests in the combined family sample.…”

Section: Discussionmentioning

confidence: 99%

“…7 The strongest evidence of linkage in the full NIMH data set was observed among LOAD families at 87.9 Mb on 9q22 with a lod score of 2.9. 6 In order to identify the LOAD gene on 9q22, recently Bertram et al 8 genotyped 19 SNPs in three positional and biological candidate genes in this region, including seven SNPs in amyloid beta precursor protein binding A1 (APBA1) at 69.3 Mb, five SNPs in Ubiquilin 1 (UBQLN1) at 83.5 Mb and seven SNPs in ATP-binding cassette A1 (ABCA1) at 104.6 Mb in the NIMH families. Two of the five SNPs in UBQLN1, intron 8 (rs12344615) and intron 9 (rs2781002), showed significant associations, which was confirmed in a second family-based sample from the Consortium on Alzheimer's Genetics (CAG) and also identified an additional significant SNP in intron 6 (rs2780995).…”

Section: Introductionmentioning

confidence: 99%

Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures

et al. 2005

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The gene coding for ubiquilin 1 (UBQLN1) is located near a linkage peak on chromosome 9q22.2 and it also impacts the function of presenilin proteins involved in early-onset Alzheimer's disease (AD). Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples. The purpose of this study was to confirm the reported association in a large case-control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-atonset (AAO), disease duration and Mini-Mental State Examination (MMSE) score. We examined the associations of three SNPs in the UBQLN1 gene (intron 6/A > C, intron 8/T > C and intron 9/ A > G) in up to 978 LOAD cases and 808 controls. All SNPs were in significant linkage disequilibrium (P < 0.0001). While modest significant associations were observed in the singlesite regression analysis, 3-site haplotype analysis revealed significant associations (P < 0.0001 for overall haplotype analysis). One common haplotype (H4) defined by intron 6/A-intron 8/Cintron 9/G alleles was associated with AD risk and one less common haplotype (H5) defined by intron 6/C-intron 8/C-intron 9/A alleles was associated with protection. The adjusted odds ratios with potentially one and two copies of risk haplotype H4 were 1.5 (95% CI: 0.99-2.26; P = 0.054) and 3.66 (95% CI: 1.43-9.39; P = 0.007), respectively, and odds ratio for haplotype H5 carriers was 0.31 (95% CI: 0.10-0.95; P = 0.0398). In addition to disease risk, the homozygosity of the risk haplotype was also associated with older AAO, longer disease duration and lower MMSE score. In summary, our data from a large case-control cohort indicate that genetic variation in the UBQLN1 gene has a modest effect on risk, AAO and disease duration of AD. Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9.

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“…For example, there is compelling biochemical evidence showing that the chymotrypsin-and PGPH-like proteasome activity are selectively impaired in AD brains (Keller et al, 2000). Recent genetic evidence also suggests a significant association between AD and various single-nucleotide polymorphisms in ubiquilin-1, which is an ubiquitin-like protein with the capacity to interact with both the proteasome and ubiquitin ligases (Bertram et al, 2005). Key aspects of AD pathology have been replicated in the 3xTg-AD mice, which provides a valuable tool for studying the molecular mechanisms by which amyloid beta (Aβ) modulates tau pathology (Oddo et al, , 2003a.…”

Section: Introductionmentioning

confidence: 99%

Aβ inhibits the proteasome and enhances amyloid and tau accumulation

Tseng

Green

Chan

et al. 2008

Neurobiology of Aging

332

255

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The accumulation of misfolded protein aggregates is a common feature of numerous neurodegenerative disorders including Alzheimer disease (AD). Here, we examined the effects of different assembly states of amyloid beta (Aβ) on proteasome function. We find that Aβ oligomers, but not monomers, inhibit the proteasome in vitro. In young 3xTg-AD mice, we observed impaired proteasome activity that correlates with the detection of intraneuronal Aβ oligomers. Blocking proteasome function in pre-pathological 3xTg-AD mice with specific inhibitors causes a marked increase in Aβ and tau accumulation, highlighting the adverse consequences of impaired proteasome activity for AD. Lastly, we show that Aβ immunotherapy in the 3xTg-AD mice reduces Aβ oligomers and reverses the deficits in proteasome activity. Taken together, our results indicate that Aβ oligomers impair proteasome activity, contributing to the age-related pathological accumulation of Aβ and tau. These findings provide further evidence that the proteasome represents a viable target for therapeutic intervention in AD.

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Family-Based Association between Alzheimer's Disease and Variants inUBQLN1

Abstract: Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.

Cited by 220 publications

References 31 publications

Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures

Aβ inhibits the proteasome and enhances amyloid and tau accumulation

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