Ubiquilin 1 polymorphisms are not associated with late‐onset Alzheimer's disease

Smemo, Scott; Nowotny, Petra; Hinrichs, Anthony L.; Kauwe, John; Cherny, Sara; Erickson, Katherine; Myers, Amanda; Kaleem, Mona; Marlowe, Lauren; Gibson, A.G.; Hollingworth, Paul; O'Donovan, Michael Conlon; Morris, Chris M.; Holmans, Peter Alan; Lovestone, Simon; Morris, John C.; Thal, Leon J.; Li, Yonghong; Grupe, Andrew; Hardy, John; Williams, Julie; Goate, Alison M.

doi:10.1002/ana.20673

Cited by 35 publications

(22 citation statements)

References 22 publications

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“…An intronic polymorphism involving alternative splicing of exon 8 in the ubiquilin 1 gene (UBQLN1), which is genetically located near a well-established linkage peak for AD on chromosome 9q22, has been associated with increased risk for lateonset AD (Bertram et al 2005). However, this finding has not been replicated by others (Smemo et al 2006).…”

Section: Significance Of Ubiquitinated Neurofibrillary Tanglesmentioning

confidence: 99%

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Ihara¹,

Morishima-Kawashima²,

Nixon³

2012

Cold Spring Harbor Perspectives in Medicine

154

126

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As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.

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Section: Significance Of Ubiquitinated Neurofibrillary Tanglesmentioning

confidence: 99%

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Ihara¹,

Morishima-Kawashima²,

Nixon³

2012

Cold Spring Harbor Perspectives in Medicine

154

126

View full text Add to dashboard Cite

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“…Although the exact role of ubiquilin 1 is unknown, it is believed to promote the accumulation of PS1 full-length protein and regulate its endoproteolysis, whereas also modulating the levels of other members of the ␥-secretase complex such as pen2 and nicastrin (14,15). Although there are contradictory data from case-control studies present (16,17), it has recently been shown that genetic variants in UBQLN1 substantially increase the risk of developing AD (18 -20). In their family-based cohort study, Bertram et al (18) have shown that several single nucleotide polymorphisms in UBQLN1 are associated with AD, one of them (UBQ-8i) leading to alternative splicing of the gene in the brain.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

“…In a search for presenilin interactors, ubiquilin 1 was identified using yeast two-hybrid, colocalization and glutathione S-transferase pull-down assays (14). Moreover, it has recently been suggested that genetic variants in UBQLN1 may be associated with an increased risk of AD (18,19,20), although other studies could not confirm the association (16,17). Very little is known so far about the function of ubiquilin 1 in the brain.…”

Section: Tablementioning

confidence: 99%

Interaction between Presenilin 1 and Ubiquilin 1 as Detected by Fluorescence Lifetime Imaging Microscopy and a High-throughput Fluorescent Plate Reader

Thomas

Herl

Spoelgen

et al. 2006

Journal of Biological Chemistry

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Presenilin 1 (PS1) in its active heterodimeric form is the catalytic center of the ␥-secretase complex, an enzymatic activity that cleaves amyloid precursor protein (APP) to produce amyloid ␤ (A␤). Ubiquilin 1 is a recently described PS1 interacting protein, the overexpression of which increases PS1 holoprotein levels and leads to reduced levels of functionally active PS1 heterodimer. In addition, it has been suggested that splice variants of the UBQLN1 gene are associated with an increased risk of developing Alzheimer disease (AD). However, it is still unclear whether PS1 and ubiquilin 1 interact when expressed at endogenous levels under normal physiological conditions. Here, we employ three novel fluorescence resonance energy transferbased techniques to investigate the interaction between PS1 and ubiquilin 1 in intact cells. We consistently find that the ubiquilin 1 N terminus is in close proximity to several epitopes on PS1. We show that ubiquilin 1 interacts both with PS1 holoprotein and heterodimer and that the interaction between PS1 and ubiquilin 1 takes place near the cell surface. Furthermore, we show that the PS1-ubiquilin 1 interaction can be detected between endogenous proteins in primary neurons in vitro as well as in brain tissue of healthy controls and Alzheimer disease patients, providing evidence of its physiological relevance.

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“…As is often the case with gene variants exerting modest effects on disease risk, subsequent genetic studies have both supported (9,10) and not supported (11,12) the initial genetic finding. Further support for the candidacy of UBQLN1 as an AD risk gene will require a comprehensive assessment of the functional role of UBQLN1 in the key pathways relevant to AD pathogenesis.…”

mentioning

confidence: 99%

Ubiquilin 1 Modulates Amyloid Precursor Protein Trafficking and Aβ Secretion

Hiltunen

Thomas

et al. 2006

Journal of Biological Chemistry

118

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Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP). For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines. We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with ␣-, ␤-, or ␥-secretase levels or activity. UBQLN1 knockdown increased the ratio of APP mature/immature, increased levels of full-length APP on the cell surface, and enhanced the secretion of sAPP (␣-and ␤-forms). Moreover, UBQLN1 knockdown increased levels of secreted A␤40 and A␤42. Finally, employing a fluorescence resonance energy transfer-based assay, we show that UBQLN1 and APP come into close proximity in intact cells, independently of the presence of the presenilins. Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic "gatekeeper" that may control APP trafficking from intracellular compartments to the cell surface. These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of A␤. Alzheimer disease (AD)3 is the most common cause of progressive neurological disorder leading to dementia. It is neuropathologically characterized by extracellular deposits of amyloid beta (A␤) peptide and by the generation of intracellular neurofibrillary tangles. Mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes are responsible for roughly half of the rare autosomal dominant, early-onset forms of the disease, which usually occur before the age of 60 (1-4). Meanwhile, apolipoprotein E (APOE) is the only commonly accepted susceptibility factor for late-onset AD (5, 6). Most mutations in APP, PSEN1, and PSEN2 genes lead to the increased production of A␤42 (relative to A␤40). A␤ is released from APP via sequential proteolytic cleavage by the ␤-and ␥-secretases (7). In addition to APP, the presenilins, and APOE, it is evident that additional AD susceptibility genes exist; successfully identifying these novel risk genes is an extremely important task that will not only facilitate prediction and diagnosis of AD but can also elucidate novel therapeutic approaches to treating and preventing AD.We have recently shown that genetic variants in the ubiquilin 1 (UBQLN1) gene, located on chromosome 9q22, increase the risk for AD, possibly by altering the expression and alternative splicing of this gene in brain (8). As is often the case with gene variants exerting modest effects on disease risk, subsequent genetic studies have both supported (9, 10) and not supported (11, 12) the initial g...

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Ubiquilin 1 polymorphisms are not associated with late‐onset Alzheimer's disease

Cited by 35 publications

References 22 publications

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Interaction between Presenilin 1 and Ubiquilin 1 as Detected by Fluorescence Lifetime Imaging Microscopy and a High-throughput Fluorescent Plate Reader

Ubiquilin 1 Modulates Amyloid Precursor Protein Trafficking and Aβ Secretion

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