Evidence map›Paper›PMID 32792571›Full record

ArticleScientific reports2020

Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia.

Maria A Telpoukhovskaia, Kai Liu, Faten A Sayed, Jon Iker Etchegaray, Min Xie, Lihong Zhan, Yaqiao Li, Yungui Zhou, David Le, Ben A Bahr and 3 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
1.2field-weighted citation impact, top 17% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 19 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Article
  6. Review
  7. Article
  8. Article
  9. Plasma Small Extracellular Vesicle Cathepsin D Dysregulation inInternational journal of molecular sciences · 2022
    Article
  10. Review
  11. Article
  12. Article
  13. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 4 institutions in 1 country.

Maria A TelpoukhovskaiaGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Kai LiuGladstone Institute of Cardiovascular Disease, San Francisco, CA, 94158, USA.
Faten A SayedGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Jon Iker EtchegarayGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Min XieGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Lihong ZhanGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Yaqiao LiGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Yungui ZhouGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
David LeGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Ben A BahrBiotechnology Research and Training Center, University of North Carolina At Pembroke, Pembroke, NC, 28372, USA.
Matthew BogyoDepartment of Pathology, Stanford University, Stanford, CA, 94305, USA.
Sheng DingGladstone Institute of Cardiovascular Disease, San Francisco, CA, 94158, USA.
Li GanGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA. lig2033@med.cornell.edu.
Gladstone Institutes · USStanford University · USUniversity of California, San Francisco · USUniversity of North Carolina at Pembroke · US

Funding

Tau acetylation in Alzheimer's diseaseR01AG054214 · NIA · WEILL MEDICAL COLL OF CORNELL UNIV · PI GAN, LI · 2017 to 2021
$3.3M
Molecular mechanisms in progranulin deficient frontotemporal dementiaR01AG051390 · NIA · WEILL MEDICAL COLL OF CORNELL UNIV · PI GAN, LI · 2015 to 2019
$2.5M
NIA NIH HHS R01 AG051390NIA NIH HHS R01 AG054214
6 · The paper itself

Abstract

Patients with frontotemporal dementia (FTD) resulting from granulin (GRN) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory and lysosomal networks. Microglia produce high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitulate inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in FTD. Limitations of current progranulin-enhancing strategies necessitate the discovery of new targets. To identify compounds that can reverse microglial defects in Grn-deficient mouse microglia, we performed a compound screen coupled with high throughput sequencing to assess key transcriptional changes in inflammatory and lysosomal pathways. Positive hits from this initial screen were then further narrowed down based on their ability to rescue cathepsin activity, a critical biochemical readout of lysosomal capacity. The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as two phenotypic modulators of progranulin deficiency. In addition, nor-BNI and DB-cAMP also rescued cell cycle abnormalities in progranulin-deficient cells. These data highlight the potential of a transcription-based platform for drug screening, and advance two novel lead compounds for FTD.

Indexed as

AnimalsBucladesineCell CycleCells, CulturedCysteine ProteasesDisease Models, AnimalFrontotemporal DementiaGene Expression ProfilingGene Expression RegulationGene Knockout TechniquesHigh-Throughput Nucleotide SequencingHumansLysosomesMiceMicrogliaModels, BiologicalBucladesineCysteine ProteasesGrn protein, mouseNaltrexonenorbinaltorphimineProgranulinsSmall Molecule Libraries

Identifiers

PMID32792571
PMCPMC7426857
OpenAlexW3048973192

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.