Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in...

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Frontotemporal dementia (FTD) linked to granulin (GRN) haploinsufficiency involves reduced progranulin levels.
• Microglia, crucial immune cells in the brain, produce progranulin and their dysfunction contributes to FTD pathogenesis.
• Current progranulin-enhancing therapies have limitations, necessitating novel therapeutic targets.

Purpose of the Study:

• To identify compounds capable of reversing microglial defects associated with progranulin deficiency.
• To establish a transcription-based drug screening platform for FTD therapeutics.
• To discover novel therapeutic leads for FTD by targeting microglial dysfunction.

Main Methods:

• A compound screen was performed on Grn-deficient mouse microglia.
• High-throughput sequencing assessed transcriptional changes in inflammatory and lysosomal pathways.
• Positive hits were validated by their ability to restore cathepsin activity and rescue cell cycle abnormalities.

Main Results:

• The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as phenotypic modulators of progranulin deficiency.
• Both compounds demonstrated efficacy in rescuing lysosomal dysfunction and cell cycle abnormalities in Grn-deficient microglia.
• The study validated a transcription-based screening approach for identifying FTD drug candidates.

Conclusions:

• Nor-BNI and DB-cAMP represent promising lead compounds for FTD treatment by targeting microglial dysfunction.
• The findings support targeting microglial progranulin insufficiency as a therapeutic strategy for FTD.
• A transcription-based screening platform can effectively identify novel compounds for neurodegenerative diseases.