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

TitleDiscovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia.
Publication TypeJournal Article
Year of Publication2020
AuthorsTelpoukhovskaia MA, Liu K, Sayed FA, Etchegaray JIker, Xie M, Zhan L, Li Y, Zhou Y, Le D, Bahr BA, Bogyo M, Ding S, Gan L
JournalSci Rep
Volume10
Issue1
Pagination13688
Date Published2020 Aug 13
ISSN2045-2322
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.

DOI10.1038/s41598-020-70534-9
Alternate JournalSci Rep
PubMed ID32792571
PubMed Central IDPMC7426857
Grant ListR01 AG051390 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
AG051390 / NH / NIH HHS / United States