↓ Skip to main content

Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism

Overview of attention for article published in Neurobiology of Aging, February 2015
Altmetric Badge

Mentioned by

facebook
2 Facebook pages

Citations

dimensions_citation
13 Dimensions

Readers on

mendeley
31 Mendeley
You are seeing a free-to-access but limited selection of the activity Altmetric has collected about this research output. Click here to find out more.
Title
Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism
Published in
Neurobiology of Aging, February 2015
DOI 10.1016/j.neurobiolaging.2014.09.001
Pubmed ID
Authors

Lies Vanden Broeck, Gernot Kleinberger, Julien Chapuis, Marc Gistelinck, Philippe Amouyel, Christine Van Broeckhoven, Jean-Charles Lambert, Patrick Callaerts, Bart Dermaut

Abstract

The human TAR DNA binding protein 43 (TDP-43), encoded by the gene TARDBP, plays a central role in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP-43 inclusions are also found in up to approximately 60% of Alzheimer's disease (AD) brains. Although ALS-causing TARDBP mutations cluster in the C-terminal glycine-rich region of the protein, the pathogenic nature of the atypical missense variants p.A90V (located between the bipartite nuclear localization signal) and p.D169G (located in the first RNA-binding domain) is unclear. In addition, whether causal ALS mutations represent gain or loss-of-function alleles remains unknown. We recently reported that loss-of-function of the highly conserved TARDBP ortholog in Drosophila (called TBPH) leads to death of bursicon neurons resulting in adult maturation and wing expansion defects. Here, we compared wild-type TARDBP, 2 typical ALS-causing mutations (p.G287S and p.A315T) and 2 atypical variants (p.A90V and p.D169G), for their ability to complement neuronal TBPH loss-of-function. Although p.D169G rescued organismal pupal lethality and neuronal loss to a similar extent as wild-type TARDBP, p.A90V, p.G287S, and p.A315T were less efficient. Accordingly, p.A90V, p.G287S, and p.A315T but not p.D169G or wild-type protein promoted a shift of TDP-43 from the nucleus to the cytoplasm in approximately 12%-14% of bursicon neurons. Finally, we found that the carrier frequency of rare variant p.A90V was higher in French-Belgian AD cases (5/1714, 0.29%) than in controls of European descent (5/9436, 0.05%) (odds ratio = 5.5; 95% confidence interval, 1.6-19.0; p = 0.009). We propose that pathogenic TARDBP mutations have partial loss-of-function properties and that TARDBP p.A90V may increase AD risk by the same mechanism.

Mendeley readers

The data shown below were compiled from readership statistics for 31 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Chile 1 3%
United Kingdom 1 3%
Unknown 29 94%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 10 32%
Researcher 7 23%
Unspecified 5 16%
Student > Master 2 6%
Student > Bachelor 2 6%
Other 5 16%
Readers by discipline Count As %
Unspecified 8 26%
Biochemistry, Genetics and Molecular Biology 8 26%
Neuroscience 5 16%
Medicine and Dentistry 4 13%
Agricultural and Biological Sciences 2 6%
Other 4 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. 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 04 December 2014.
All research outputs
#9,460,743
of 11,842,719 outputs
Outputs from Neurobiology of Aging
#2,627
of 2,912 outputs
Outputs of similar age
#173,227
of 256,852 outputs
Outputs of similar age from Neurobiology of Aging
#92
of 97 outputs
Altmetric has tracked 11,842,719 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,912 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.2. This one is in the 5th percentile – i.e., 5% of its peers scored the same or lower than it.
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 256,852 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 19th percentile – i.e., 19% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 97 others from the same source and published within six weeks on either side of this one. This one is in the 5th percentile – i.e., 5% of its contemporaries scored the same or lower than it.