Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia
| Autor: | Yungui Zhou, Lihong Zhan, Ben A. Bahr, Sheng Ding, David Le, Maria Telpoukhovskaia, Min Xie, Jon Iker Etchegaray, Yaqiao Li, Faten A. Sayed, Matthew Bogyo, Li Gan, Kai Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Granulin lcsh:Medicine Transcriptome Gene Knockout Techniques Mice Progranulins 0302 clinical medicine Cysteine Proteases lcsh:Science Cells Cultured Multidisciplinary Microglia Drug discovery Cell Cycle Neurodegenerative diseases Neurodegeneration High-throughput screening High-Throughput Nucleotide Sequencing Cell cycle Naltrexone Cell biology medicine.anatomical_structure Drug screening Frontotemporal Dementia medicine.symptom Haploinsufficiency Inflammation Biology Models Biological Article Small Molecule Libraries 03 medical and health sciences mental disorders medicine Animals Humans Cathepsin Sequence Analysis RNA Gene Expression Profiling lcsh:R medicine.disease Disease Models Animal 030104 developmental biology Bucladesine Gene Expression Regulation lcsh:Q Lysosomes 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-70534-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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