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Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity

Overview of attention for article published in Acta Neuropathologica Communications, May 2018
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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 (83rd percentile)

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Title
Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity
Published in
Acta Neuropathologica Communications, May 2018
DOI 10.1186/s40478-018-0545-x
Pubmed ID
Authors

Alexandra M. Nicholson, Xiaolai Zhou, Ralph B. Perkerson, Tammee M. Parsons, Jeannie Chew, Mieu Brooks, Mariely DeJesus-Hernandez, NiCole A. Finch, Billie J. Matchett, Aishe Kurti, Karen R. Jansen-West, Emilie Perkerson, Lillian Daughrity, Monica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Fenghua Hu, Tania F. Gendron, Melissa E. Murray, Dennis W. Dickson, John D. Fryer, Leonard Petrucelli, Rosa Rademakers

Abstract

Loss-of-function mutations in progranulin (GRN) and a non-coding (GGGGCC)n hexanucleotide repeat expansions in C9ORF72 are the two most common genetic causes of frontotemporal lobar degeneration with aggregates of TAR DNA binding protein 43 (FTLD-TDP). TMEM106B encodes a type II transmembrane protein with unknown function. Genetic variants in TMEM106B associated with reduced TMEM106B levels have been identified as disease modifiers in individuals with GRN mutations and C9ORF72 expansions. Recently, loss of Tmem106b has been reported to protect the FTLD-like phenotypes in Grn-/- mice. Here, we generated Tmem106b-/- mice and examined whether loss of Tmem106b could rescue FTLD-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Our results showed that neither partial nor complete loss of Tmem106b was able to rescue behavioral deficits induced by the expression of (GGGGCC)66 repeats (66R). Loss of Tmem106b also failed to ameliorate 66R-induced RNA foci, dipeptide repeat protein formation and pTDP-43 pathological burden. We further found that complete loss of Tmem106b increased astrogliosis, even in the absence of 66R, and failed to rescue 66R-induced neuronal cell loss, whereas partial loss of Tmem106b significantly rescued the neuronal cell loss but not neuroinflammation induced by 66R. Finally, we showed that overexpression of 66R did not alter expression of Tmem106b and other lysosomal genes in vivo, and subsequent analyses in vitro found that transiently knocking down C9ORF72, but not overexpression of 66R, significantly increased TMEM106B and other lysosomal proteins. In summary, reducing Tmem106b levels failed to rescue FTLD-like phenotypes in a mouse model mimicking the toxic gain-of-functions associated with overexpression of 66R. Combined with the observation that loss of C9ORF72 and not 66R overexpression was associated with increased levels of TMEM106B, this work suggests that the protective TMEM106B haplotype may exert its effect in expansion carriers by counteracting lysosomal dysfunction resulting from a loss of C9ORF72.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 35 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 35 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 6 17%
Student > Bachelor 4 11%
Researcher 4 11%
Other 3 9%
Student > Doctoral Student 3 9%
Other 5 14%
Unknown 10 29%
Readers by discipline Count As %
Neuroscience 10 29%
Biochemistry, Genetics and Molecular Biology 5 14%
Medicine and Dentistry 5 14%
Agricultural and Biological Sciences 2 6%
Social Sciences 1 3%
Other 2 6%
Unknown 10 29%

Attention Score in Context

This research output has an Altmetric Attention Score of 12. 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 12 March 2020.
All research outputs
#1,812,857
of 17,370,809 outputs
Outputs from Acta Neuropathologica Communications
#304
of 1,061 outputs
Outputs of similar age
#47,251
of 287,827 outputs
Outputs of similar age from Acta Neuropathologica Communications
#1
of 1 outputs
Altmetric has tracked 17,370,809 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 1,061 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 11.4. This one has gotten more attention than average, scoring higher than 70% 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 287,827 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 83% of its contemporaries.
We're also able to compare this research output to 1 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them