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Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy

Overview of attention for article published in Cellular & Molecular Life Sciences, August 2017
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  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (79th percentile)
  • High Attention Score compared to outputs of the same age and source (84th percentile)

Mentioned by

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12 tweeters
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1 Facebook page

Citations

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3 Dimensions

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16 Mendeley
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Title
Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy
Published in
Cellular & Molecular Life Sciences, August 2017
DOI 10.1007/s00018-017-2632-8
Pubmed ID
Authors

Albert Lee, Stephanie L. Rayner, Serene S. L. Gwee, Alana De Luca, Hamideh Shahheydari, Vinod Sundaramoorthy, Audrey Ragagnin, Marco Morsch, Rowan Radford, Jasmin Galper, Sarah Freckleton, Bingyang Shi, Adam K. Walker, Emily K. Don, Nicholas J. Cole, Shu Yang, Kelly L. Williams, Justin J. Yerbury, Ian P. Blair, Julie D. Atkin, Mark P. Molloy, Roger S. Chung

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase (SCF(cyclin F)) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin-proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin F(S621G) caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin F(WT). Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin F(S621G)-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin F(S621G) revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal-lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin F(S621G) disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis.

Twitter Demographics

The data shown below were collected from the profiles of 12 tweeters 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 16 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 16 100%

Demographic breakdown

Readers by professional status Count As %
Unspecified 5 31%
Student > Ph. D. Student 4 25%
Student > Master 3 19%
Professor 2 13%
Student > Doctoral Student 1 6%
Other 1 6%
Readers by discipline Count As %
Unspecified 6 38%
Biochemistry, Genetics and Molecular Biology 5 31%
Agricultural and Biological Sciences 3 19%
Neuroscience 2 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 9. 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 26 October 2018.
All research outputs
#1,715,918
of 12,413,219 outputs
Outputs from Cellular & Molecular Life Sciences
#257
of 2,463 outputs
Outputs of similar age
#53,757
of 266,985 outputs
Outputs of similar age from Cellular & Molecular Life Sciences
#9
of 58 outputs
Altmetric has tracked 12,413,219 research outputs across all sources so far. Compared to these this one has done well and is in the 86th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,463 research outputs from this source. They receive a mean Attention Score of 3.9. This one has done well, scoring higher than 89% 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 266,985 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 79% of its contemporaries.
We're also able to compare this research output to 58 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 84% of its contemporaries.