Key Findings
Researchers have identified the FASN-SREBP1 axis as a candidate therapeutic pathway in Parkinson’s disease. By conducting a phenotypic screen of 4,108 compounds in GBA-N370S (GBA-NS) induced pluripotent stem cell dopaminergic neurons (iPSC-DANs), the study identified fatty acid synthase (FASN) as the most enriched protein target. The results indicate that FASN inhibition increases intracellular calcium release, increases active β-glucocerebrosidase (GCase), and reduces both ER stress and extracellular α-synuclein release.
Technical Details
The study utilized calcium dyshomeostasis as the primary phenotype for screening, as GBA-N370S iPSC-DANs exhibit impaired intracellular calcium release. The correlation between the ability of compounds to rescue calcium release and biochemical potency against FASN was confirmed across multiple chemical series. Mechanistically, FASN inhibition activated sterol regulatory element-binding protein 1 (SREBP1). The researchers found that SREBP1 overexpression alone was sufficient to increase intracellular calcium release, establishing a FASN-SREBP1-calcium homeostasis axis in human neurons.
To validate these findings in vivo, the FASN inhibitor BI 99179 was administered to a Parkinson’s mouse model. The inhibitor achieved brain exposure, reduced brain fatty acid levels, and induced an SRE-associated transcriptional response.
Background & Context
Modeling Parkinson’s disease in vitro is challenging, particularly when seeking robust functional phenotypes for target discovery. Patient-derived iPSC-DANs offer a platform to address this, specifically by leveraging known pathophysiology such as calcium dyshomeostasis. Untargeted lipidomics were employed in this study to demonstrate broad remodelling of the neuronal lipidome following FASN inhibition, confirming target engagement.
Significance & Outlook
This research establishes that functional screening in patient iPSC-neurons is a viable discovery platform for identifying targets that can be transitioned to in vivo models. By nominating the FASN-SREBP1 axis, the study provides a potential new direction for therapeutic intervention in PD, specifically targeting lipid-calcium regulatory mechanisms to rescue multiple pathogenic pathways.
Source: https://doi.org/10.64898/2026.10.27.761977
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