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Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations

Overview of attention for article published in Molecular Neurodegeneration, July 2015
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (84th percentile)

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1 news outlet
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1 tweeter

Citations

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18 Dimensions

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42 Mendeley
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Title
Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations
Published in
Molecular Neurodegeneration, July 2015
DOI 10.1186/s13024-015-0024-9
Pubmed ID
Authors

Karolien Bettens, Steven Vermeulen, Caroline Van Cauwenberghe, Bavo Heeman, Bob Asselbergh, Caroline Robberecht, Sebastiaan Engelborghs, Mathieu Vandenbulcke, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Christine Van Broeckhoven, Kristel Sleegers

Abstract

The clusterin (CLU) gene has been identified as an important risk locus for Alzheimer's disease (AD). Although the actual risk-increasing polymorphisms at this locus remain to be identified, we previously observed an increased frequency of rare non-synonymous mutations and small insertion-deletions of CLU in AD patients, which specifically clustered in the β-chain domain of CLU. Nonetheless the pathogenic nature of these variants remained unclear. Here we report a novel non-synonymous CLU mutation (p.I360N) in a Belgian Alzheimer patient and have explored the pathogenic nature of this and 10 additional CLU mutations on protein localization and secretion in vitro using immunocytochemistry, immunodetection and ELISAs. Three patient-specific CLU mutations in the β-chain (p.I303NfsX13, p.R338W and p.I360N) caused an alteration of the subcellular CLU localization and diminished CLU transport through the secretory pathway, indicative of possible degradation mechanisms. For these mutations, significantly reduced CLU intensity was observed in the Golgi while almost all CLU protein was exclusively present in the endoplasmic reticulum. This was further confirmed by diminished CLU secretion in HEK293T and HEK293 FLp-In cell lines. Our data lend further support to the contribution of rare coding CLU mutations in the pathogenesis of neurodegenerative diseases. Functional analyses suggest reduced secretion of the CLU protein as the mode of action for three of the examined CLU mutations. One of those is a frameshift mutation leading to a loss of secreted protein, and the other two mutations are amino acid substitutions in the disulfide bridge region, possibly interfering with heterodimerization of the α- and β-chain of CLU.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Unknown 41 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 14 33%
Researcher 11 26%
Student > Bachelor 6 14%
Student > Master 4 10%
Other 3 7%
Other 2 5%
Unknown 2 5%
Readers by discipline Count As %
Agricultural and Biological Sciences 15 36%
Neuroscience 10 24%
Medicine and Dentistry 7 17%
Biochemistry, Genetics and Molecular Biology 6 14%
Psychology 1 2%
Other 1 2%
Unknown 2 5%

Attention Score in Context

This research output has an Altmetric Attention Score of 10. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 24 July 2015.
All research outputs
#534,602
of 5,393,711 outputs
Outputs from Molecular Neurodegeneration
#71
of 311 outputs
Outputs of similar age
#25,998
of 175,172 outputs
Outputs of similar age from Molecular Neurodegeneration
#13
of 19 outputs
Altmetric has tracked 5,393,711 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 311 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.9. This one has gotten more attention than average, scoring higher than 72% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 175,172 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 84% of its contemporaries.
We're also able to compare this research output to 19 others from the same source and published within six weeks on either side of this one. This one is in the 26th percentile – i.e., 26% of its contemporaries scored the same or lower than it.