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Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia

Overview of attention for article published in Molecular Neurodegeneration, June 2016
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (90th percentile)
  • High Attention Score compared to outputs of the same age and source (99th percentile)

Mentioned by

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2 news outlets
twitter
4 tweeters

Citations

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53 Dimensions

Readers on

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100 Mendeley
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Title
Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia
Published in
Molecular Neurodegeneration, June 2016
DOI 10.1186/s13024-016-0114-3
Pubmed ID
Authors

Christopher J. Holler, Georgia Taylor, Zachary T. McEachin, Qiudong Deng, William J. Watkins, Kathryn Hudson, Charles A. Easley, William T. Hu, Chadwick M. Hales, Wilfried Rossoll, Gary J. Bassell, Thomas Kukar

Abstract

Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases. Here, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat multiple neurodegenerative diseases.

Twitter Demographics

The data shown below were collected from the profiles of 4 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 100 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Denmark 1 1%
Unknown 99 99%

Demographic breakdown

Readers by professional status Count As %
Researcher 25 25%
Student > Ph. D. Student 14 14%
Other 12 12%
Student > Bachelor 10 10%
Student > Postgraduate 7 7%
Other 19 19%
Unknown 13 13%
Readers by discipline Count As %
Neuroscience 20 20%
Biochemistry, Genetics and Molecular Biology 19 19%
Agricultural and Biological Sciences 16 16%
Medicine and Dentistry 9 9%
Pharmacology, Toxicology and Pharmaceutical Science 6 6%
Other 14 14%
Unknown 16 16%

Attention Score in Context

This research output has an Altmetric Attention Score of 18. 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 July 2016.
All research outputs
#1,282,831
of 17,361,274 outputs
Outputs from Molecular Neurodegeneration
#77
of 684 outputs
Outputs of similar age
#26,371
of 268,242 outputs
Outputs of similar age from Molecular Neurodegeneration
#1
of 5 outputs
Altmetric has tracked 17,361,274 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 684 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.4. This one has done well, scoring higher than 88% 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 268,242 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 90% of its contemporaries.
We're also able to compare this research output to 5 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