Phenotypic screening in Parkinson's iPSC-dopamine neurons identifies the FASN-SREBP1 axis as a potential therapeutic target

In GBA-N370S iPSC-dopaminergic neurons, a 4,108-compound screen linked rescued intracellular calcium release to FASN inhibition and implicated the FASN–SREBP1 axis.

• Why it matters: Robust functional phenotypes are difficult to obtain for in vitro Parkinson’s disease target discovery, and calcium dyshomeostasis provides a disease-relevant readout to screen therapeutics.
• What they did: The authors screened 4,108 compounds in GBA-N370S iPSC-DANs for calcium-release rescue, then validated on-target activity with FASN knockdown, untargeted lipidomics, and mechanistic testing of SREBP1.
• The result: FASN inhibition activated SREBP1 and increased calcium release, while BI 99179 showed brain exposure, reduced brain fatty acid levels, and induced an SREBP-associated transcriptional response in a Parkinson’s mouse model.

AI summary of the abstract · may contain errors · not medical advice · read the paper.